Annrheumdis 2020 218636.full

University of Southern Denmark
Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred

DNA sequencing
Sandling, Johanna K.; Pucholt, Pascal; Hultin Rosenberg, Lina; Farias, Fabiana H.G.;
Kozyrev, Sergey V.; Eloranta, Maija Leena; Alexsson, Andrei; Bianchi, Matteo; Padyukov,
Leonid; Bengtsson, Christine; Jonsson, Roland; Omdal, Roald; Lie, Benedicte A.; Massarenti,
Laura; Steffensen, Rudi; Jakobsen, Marianne A.; Lillevang, Søren T.; Lerang, Karoline;
Molberg, Øyvind; Voss, Anne; Troldborg, Anne; Jacobsen, Søren; Syvänen, Ann Christine;
Jönsen, Andreas; Gunnarsson, Iva; Svenungsson, Elisabet; Rantapää-Dahlqvist, Solbritt;
Bengtsson, Anders A.; Sjöwall, Christopher; Leonard, Dag; Lindblad-Toh, Kerstin; Rönnblom,
Lars
Published in:
Annals of the Rheumatic Diseases
DOI:
10.1136/annrheumdis-2020-218636
Publication date:
2021
Document version:
Final published version
Document license:
CC BY
Citation for pulished version (APA):

Sandling, J. K., Pucholt, P., Hultin Rosenberg, L., Farias, F. H. G., Kozyrev, S. V., Eloranta, M. L., Alexsson, A.,
Bianchi, M., Padyukov, L., Bengtsson, C., Jonsson, R., Omdal, R., Lie, B. A., Massarenti, L., Steffensen, R.,
Jakobsen, M. A., Lillevang, S. T., Lerang, K., Molberg, Ø., ... Rönnblom, L. (2021). Molecular pathways in
patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing. Annals of the
Rheumatic Diseases, 80(1), 109-117. https://doi.org/10.1136/annrheumdis-2020-218636
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Systemic lupus erythematosus
Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218636 on 9 October 2020. Downloaded from http://ard.bmj.com/ on December 7, 2020 by guest. Protected by copyright.
TRANSLATIONAL SCIENCE
Molecular pathways in patients with systemic lupus

erythematosus revealed by gene-centred
DNA sequencing
Johanna K Sandling ‍ ‍,1 Pascal Pucholt ‍ ‍,1 Lina Hultin Rosenberg,2
Fabiana H G Farias,2,3 Sergey V Kozyrev,2 Maija-Leena Eloranta,1 Andrei Alexsson,1
Matteo Bianchi,2 Leonid Padyukov,4 Christine Bengtsson,5 Roland Jonsson,6
Roald Omdal,6,7 Benedicte A Lie,8 Laura Massarenti,9 Rudi Steffensen,10
Marianne A Jakobsen,11 Søren T Lillevang,11 on behalf of the ImmunoArray
Development Consortium and DISSECT consortium, Karoline Lerang,12
Øyvind Molberg,12,13 Anne Voss,14 Anne Troldborg,15,16 Søren Jacobsen,17,18
Ann-Christine Syvänen,19 Andreas Jönsen,20 Iva Gunnarsson,4
Elisabet Svenungsson ‍ ‍,4 Solbritt Rantapää-Dahlqvist,5 Anders A Bengtsson,20
Christopher Sjöwall ‍ ‍,21 Dag Leonard,1 Kerstin Lindblad-Toh,2,22 Lars Rönnblom ‍ ‍1
Handling editor Josef S ABSTRACT

Smolen Key messages
Objectives Systemic lupus erythematosus (SLE) is an
►► Additional material is
autoimmune disease with extensive heterogeneity in
What is already known about this subject?
published online only. To view, disease presentation between patients, which is likely
►► The clinical heterogeneity in systemic lupus
please visit the journal online due to an underlying molecular diversity. Here, we aimed
(http://d x.doi.o rg/10.1136/ erythematosus (SLE) is likely due to an
at elucidating the genetic aetiology of SLE from the
annrheumdis-2020-218636). underlying molecular diversity that could have
immunity pathway level to the single variant level, and
implications for therapy.
For numbered affiliations see stratify patients with SLE into distinguishable molecular
►► In recent years, gene expression, autoantibody
end of article. subgroups, which could inform treatment choices in SLE.
profiles and cytokine levels have been used
Methods We undertook a pathway-centred approach,
to identify groups of patients with SLE with
Correspondence to using sequencing of immunological pathway genes.
Dr Johanna K Sandling and distinct molecular disease mechanisms.
Altogether 1832 candidate genes were analysed in 958
Professor Lars Rönnblom,
Swedish patients with SLE and 1026 healthy individuals.
Department of Medical Sciences, What does this study add?
Rheumatology, Rudbeck Aggregate and single variant association testing was
►► We have presented a novel strategy to
laboratory C11, Uppsala performed, and we generated pathway polygenic risk
genetically stratify SLE patients according to
University, Uppsala 75185, scores (PRS).
Sweden; involved molecular pathways.
Results We identified two main independent pathways
johanna.sandling@m edsci.uu. ►► Using genetic information to stratify patients
se, involved in SLE susceptibility: T lymphocyte differentiation
would have the advantages of providing stable
Lars.Ronnblom@m edsci.uu.se and innate immunity, characterised by HLA and
molecular markers for early classification.
interferon, respectively. Pathway PRS defined pathways
Received 20 July 2020 in individual patients, who on average were positive for
Revised 15 September 2020 How might this impact on clinical practice or
seven pathways. We found that SLE organ damage was
Accepted 16 September 2020 future developments?
more pronounced in patients positive for the T or B cell
►► Our results show that pathway risk scores have
receptor signalling pathways. Further, pathway PRS-
the potential to stratify SLE patients beyond
based clustering allowed stratification of patients into
clinical manifestations into molecular subsets,
four groups with different risk score profiles. Studying
which may have implications for clinical follow-
sets of genes with priors for involvement in SLE, we
up and therapy selection.
observed an aggregate common variant contribution to
SLE at genes previously reported for monogenic SLE as
well as at interferonopathy genes.
nucleic acids and associated proteins, immune
© Author(s) (or their
Conclusions Our results show that pathway risk scores
complex formation and inflammation in multiple
employer(s)) 2020. Re-use have the potential to stratify patients with SLE beyond
organs. There is a wide spectrum of clinical mani-
permitted under CC BY. clinical manifestations into molecular subsets, which
Published by BMJ. festations in SLE and extensive heterogeneity in
may have implications for clinical follow-up and therapy
disease presentation between patients; in addition,
To cite: Sandling JK, selection.
the treatment response is often unpredictable.1
Pucholt P, Hultin
Rosenberg L, et al.
The pathogenesis of SLE has partially been clari-
Ann Rheum Dis Epub ahead fied during the last years, and important features
of print: [please include Day INTRODUCTION are increased expression of type I interferon (IFN)
Month Year]. doi:10.1136/ Systemic lupus erythematosus (SLE) is character- regulated genes, defects in the apoptotic process
annrheumdis-2020-218636 ised by the production of autoantibodies targeting and activated autoreactive B cells.1 2 The reasons
Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi:10.1136/annrheumdis-2020-218636 1
behind these abnormalities are both environmental and genetic, Genetic association analyses
and today around 100 SLE susceptibility loci have been iden- Several variant sets were generated for aggregate association
tified.3 4 Monogenic forms of SLE exist, but for a majority of testing: (1) 1832 individual gene variant sets; (2) 35 pathway
patients the environment and the cumulative number of suscep- variant sets based on the Kyoto Encyclopaedia of Genes and
tibility alleles will influence the risk of developing the disease.4 5 Genomes (KEGG)20 ; (3) five literature review gene sets: the
To date, the contribution of rare genetic variants and the type I interferon pathway,21 interferonopathy genes,22 23 SLE
impact of regulatory variants have not been widely explored in Genome-Wide Association Study (GWAS) genes,3 4 the comple-
SLE. DNA sequencing has the potential to discover novel SLE ment subset of KEGG hsa04610 and genes causing monogenic
associated variants not captured by genotyping arrays. Due to SLE or lupus-like disease.24 Aggregate association testing was
the high cost, whole genome sequencing studies (WGS) in SLE performed using Sequence Kernel Association Optimal Test
have so far mainly focused on families or smaller samples, as (SKAT-O) or GenePy.25 26 Single variant association analyses were
have exome sequencing studies (WES).6–9 Today it is feasible performed in PLINK. SLE case-only variants were identified by
to perform targeted sequencing in larger cohorts; however, the removing all SNVs present in our Swedish control dataset, the
number of such studies focusing on SLE is still limited.10 Addi- SweGen project or the Genome Aggregation Database European
tionally, association analysis for rare variants discovered through non-Finnish controls.27 28
sequencing is hampered by low statistical power. Aggregating
variants on the gene level or by molecular pathway information Risk scores and cluster analysis
is one approach to increase power and gain biological insight Cumulative pathway SLE polygenic risk scores (pathway PRSs)
from rare variants.11 were assigned to each individual based on SNVs associated with
The clinical heterogeneity in SLE is likely due to an underlying SLE at nominal significance. For each independent SNV the
molecular diversity that could have implications for therapy. natural logarithm of the OR for SLE susceptibility was multi-
In recent years this has started to be addressed, mainly using plied by the number of minor alleles in each individual. The sum
gene expression, autoantibody profiles and cytokines to iden- of all products of all genes in each of the 35 KEGG pathways for
tify groups of patients with SLE with distinct molecular disease each patient was defined as the individual pathway PRS. Hier-
mechanisms.12–14 Using genetic information to stratify patients archical cluster analysis of pathway PRSs was used to identify
would have the advantage of providing stable molecular markers groups of patients with SLE.
for early classification.
Here, we performed targeted sequencing of regulatory and
Replication study and meta-analysis
coding regions in a Swedish SLE case–control cohort. We aimed
Replication genotyping in individuals from Norway and Denmark
at elucidating the genetic aetiology of SLE from the immunity
was performed using the MassARRAY system. The Swedish SLE
pathway level to the single variant level, and stratify patients
case–control study was expanded to include an additional 1000
with SLE into molecular subgroups. Altogether around 9% of
control individuals.27 The Scandinavian meta-analysis included
all genes in the human genome were analysed based on their
1794 patients with SLE and 3241 control individuals.
role in immune-mediated diseases. Gene regions were extended
to include promoters and other potentially regulatory elements
based on mammalian conservation.15 RESULTS
We performed a DNA sequencing study in SLE to study immu-
nity pathways, an overview of analyses can be found in online
METHODS supplemental figure S2.
For full details on methods see online supplemental methods.
T lymphocyte differentiation and innate immunity pathways
Subjects and DNA samples are associated with SLE
The Swedish SLE cohorts included patients recruited at five rheu- The sequencing data analysis focused on 1832 genes with rele-
matology clinics and the controls were healthy blood donors and vance for immune-mediated diseases. These genes mainly belong
population controls. The quality-controlled dataset comprised to 35 molecular signalling pathways as defined by the KEGG
958 patients with SLE and 1026 control individuals. Patients database (online supplemental table S2).20 Using an aggregate
with SLE fulfilled at least four of the classification criteria for test for all variants in the genes belonging to each pathway, we
SLE as defined by the American College of Rheumatology found that 21 of the tested pathways were associated with SLE
(ACR).16 17 Clinical characteristics of the patients are available in (false discovery rate (FDR) <0.05, table 1 and online supple-
online supplemental tables S1A and B. mental table S3). The most significantly associated pathways
included T helper cell differentiation pathways, with Th1 and
Th2 cell differentiation as the top result (FDRTh1-2=2.2×10-9;
Targeted DNA sequencing analysis FDRTh17=1.5×10-8), followed by antigen processing and presen-
Targeted DNA sequencing was performed in the Swedish SLE tation (FDR=3.1×10-9).
case–control cohorts. A SeqCap EZ Choice XL sequence capture We next explored a sequential elimination strategy to iden-
panel was designed, libraries were prepared as described else- tify independent pathway associations. First, removing all Th1
where18 and sequenced on an Illumina HiSeq 2500. An overview and Th2 pathway genes in the pathway aggregate association
of the variant discovery and quality control steps can be found test resulted in the antigen processing and presentation pathway
in online supplemental figure S1. Study subjects falling outside as the top result (FDR=4.8×10-6). Second, antigen processing
of the European subpopulation of the Human Genome Diver- and presentation as well as Th1 and Th2 pathway genes were
sity Project (HGDP) reference set were excluded (online supple- removed, which resulted in Complement and coagulation
mental figure S7).19 The quality- controlled dataset contained cascades as the top result (FDR=0.0091). Third, also genes in this
287 354 single-nucleotide variants (SNVs) and covered 1832 of pathway were removed, and the janus kinase-signal transducers
the targeted gene regions. and activators of transcription (JAK-STAT) pathway became the
2 Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi:10.1136/annrheumdis-2020-218636
Table 1 SLE case–control pathway based aggregate association analysis
Pathway Genes in pathway Genes in test SNVs in test P value* FDR†
Th1 and Th2 cell differentiation (hsa04658) 92 78 14 362 6.3E-11 2.2E-09
Antigen processing and presentation (hsa04612) 77 40 8017 1.8E-10 3.1E-09
Hematopoietic cell lineage (hsa04640) 97 71 13 013 3.8E-10 4.5E-09
Th17 cell differentiation (hsa04659) 107 96 19 347 1.7E-09 1.5E-08
Intestinal immune network for IgA production (hsa04672) 49 39 7909 3.4E-08 2.4E-07
Natural killer cell-mediated cytotoxicity (hsa04650) 131 100 15 821 4.7E-06 2.8E-05
TNF signalling pathway (hsa04668) 112 88 12 639 1.9E-05 9.4E-05
JAK-STAT signalling pathway (hsa04630) 162 133 18 003 7.4E-05 0.00032
RIG-I-like receptor signalling pathway (hsa04622) 70 63 8459 0.00021 0.00080
NOD-like receptor signalling pathway (hsa04621) 178 109 15 729 0.00031 0.0011
Complement and coagulation cascades (hsa04610) 79 50 7112 0.00041 0.0013
Toll-like receptor signalling pathway (hsa04620) 104 96 12 178 0.00080 0.0022
Cytokine-cytokine receptor interaction (hsa04060) 294 221 26 771 0.00083 0.0022
C-type lectin receptor signalling pathway (hsa04625) 104 75 12 986 0.0020 0.0050
IL-17 signalling pathway (hsa04657) 93 68 9358 0.0043 0.0100
Fc epsilon RI signalling pathway (hsa04664) 68 51 8514 0.0052 0.011
Viral protein interaction with cytokine and receptor (hsa04061) 100 75 8435 0.0062 0.013
NF-kappa B signalling pathway (hsa04064) 102 88 14 349 0.0078 0.015
Osteoclast differentiation (hsa04380) 128 101 18 602 0.013 0.023
T cell receptor signalling pathway (hsa04660) 103 85 14 268 0.014 0.025
Cytosolic DNA-sensing pathway (hsa04623) 63 40 4993 0.015 0.025
Pathways with FDR <0.05 in the association analysis including all genes are presented.
*SKAT-O SLE case-control association p value.
†SKAT-O SLE case–control association FDR.
FDR, false discovery rate; IL-17, interleukin 17; NF, nuclear factor; NOD, nucleotide-binding oligomerisation domain; RIG, retinoic acid-inducible gene; SKAT-O, sequence kernel
association optimal test; SLE, systemic lupus erythematosus; SNV, single-nucleotide polymorphism; TNF, tumour necrosis factor.
top result (FDR=0.014). Lastly, when removing genes in all for the pathway PRS for seven pathways (figure 2B). As we had
these four pathways no significant pathways remained. Thus, previously observed that a high SLE genetic risk score was asso-
our data point to two main routes with genetic evidence of associated with organ damage in SLE, we investigated whether this
ciation to SLE: T cell differentiation and innate immunity. could be observed for specific pathways.5 We found that the SLE
To identify the genes that underlie the association signals in International Collaborating Clinics Damage Index was signifi-
the T-cell differentiation, antigen processing and presentation, cantly higher in the SLE patients positive for the T cell or B cell
Complement and coagulation and JAK-STAT pathways, gene- receptor signalling pathways (figure 3A,B). No other pathways
based association testing was performed (figure 1). The top were associated with clinical manifestations of SLE or survival.
association for the JAK-STAT pathway originated from the IFN We then performed a hierarchical cluster analysis on the
kappa (IFNK) gene region. SLE-associated genes in the T cell pathway PRSs in SLE, to identify groups of patients with similar
differentiation and antigen processing and presentation path- molecular aetiology. Four clusters of patients were identified
ways were dominated by genes in the HLA region, and for the (figure 4). The pathway with the most significant difference in
complement and coagulation cascade pathway, complement PRS between clusters was the antigen processing and presen-
genes located in the HLA region were highly significantly asso- tation pathway, followed by Th17 cell differentiation (online
ciated with SLE. supplemental figure S4). Next, we investigated whether the
molecular stratification of patients with SLE also mirrored differ-
Pathway PRS define subsets of patients with SLE ences in clinical presentation between groups. We found that the
Having identified pathways with genetic association with SLE, presence of autoantibodies against Sjögren’s syndrome-related
we hypothesised that different patients with SLE could have antigens SSA and/or SSB was more common among patients in
distinct pathways affected. We constructed pathway PRS for clusters 3 and 4 (figure 3C). We did not observe any significant
each individual and each of the pathways, by combining the difference in other clinical features, including survival, between
burden of common SLE associated alleles from our sequencing the four patient clusters.
data. Individuals with a pathway PRS higher than that observed
for the 97.5th percentile of control individuals were classified Common variants contribute risk at monogenic risk loci in SLE
as positive for that pathway (online supplemental figure S3). We then focused our analysis on gene-sets with prior evidence
The largest proportion of positive SLE patients was observed for involvement in SLE, but which were not defined in KEGG,
for the Cytokine-cytokine receptor interaction pathway (41%, to investigate the impact of both rare and common variants for
figure 2A, and online supplemental table S4). For the Th1 and these groups of genes. We found that interferon system, inter-
Th2 cell differentiation, antigen processing and presentation, feronopathy, SLE GWAS, complement system and monogenic
Complement and coagulation cascades and JAK-STAT signalling SLE and lupus-like disease genes in aggregate were associated
pathways 18%, 16%, 21% and 29% of patients with SLE were with SLE when analysing variants of all minor allele frequen-
positive, respectively. On average each SLE patient tested positive cies (MAF) (table 2 and online supplemental table S5). Only the
Figure 1 Results of SLE case–control gene-based association analyses. P values for association plotted against chromosomal location, where
each point represents a gene region. The line indicates a false discovery rate of 5%. The y-axis has been cut at p=1×10-15. Genes belonging to
the T-cell differentiation (Th1 and Th2), antigen processing and presentation, complement and coagulation or JAK-STAT signalling pathways are
highlighted, and their most significant genes or gene regions are indicated by name. IFNK, interferon kappa; IL21, interleukin 21; SLE, systemic lupus
erythematosus.
monogenic SLE and lupus-like disease gene-set was significantly we observed SNV associations at three potentially novel SLE risk
associated with SLE when separately analysing the rarer variant loci, CAPN13, MOB3B/IFNK and HAL, at a suggestive signifi-
(MAF <0.01) contribution (table 2). There was a clear common cance threshold (p<1×10-4, online supplemental figure 5B–E,
variant (MAF >0.05) contribution to associations for the inter- table S8). As the association signals at CAPN13, MOB3B/IFNK
feronopathy, SLE GWAS, complement system and monogenic and HAL had not been reported in SLE GWAS in other ances-
SLE and lupus-like disease gene-sets (table 2). tries, we attempted to replicate these findings in additional
Scandinavian SLE cases and controls (online supplemental table
Potentially novel SLE risk loci S1A). However, we did not find additional support for a role of
Next, we asked whether we could detect novel SLE risk loci, SNVs at these novel loci in SLE (online supplemental table S9).
regardless of pathway or gene-set membership. Two potentially
novel gene regions passed a Bonferroni corrected threshold in Patients with SLE carry unique coding variants
the gene-based SLE case–control association analyses: PABPC4 We next investigated whether there was an increased rare coding
(p=4.3×10-8) and IFNK (p=1.2×10-5, online supplemental mutational burden for patients with SLE at the 1832 genes.
figure 5A, tables S6 and S7). In single variant association analyses, We observed that all individuals carried rare non-synonymous
Figure 2 Pathway SLE polygenic risk scores. (A) Illustrates pathway Polygenic Risk Scores (PRS) for the Cytokine–cytokine receptor interaction
pathway. P values represent differences in PRS between patients with SLE (SLE) and healthy control individuals (HC). The dashed line indicates the
PRS 97.5 percentile in control individuals. (B) The number of pathways each individual patient with SLE tested positive for using the pathway PRS. On
average patients were positive for 7.2 pathways. SLE, systemic lupus erythematosus.
Figure 3 Pathway SLE polygenic risk scores grouping and clustering. (A, B) The Systemic Lupus Erythematosus International Collaborating Clinics
(SLICC) damage index for patients with SLE positive and negative for the T cell receptor and B cell receptor signalling pathways. P values represent
differences in Damage Index between pathway positive and negative patients, uncorrected p values are presented (Bonferroni corrected threshold
p=0.00143). (C) Prevalence of Sjögren’s syndrome (SSA and/or SSB) autoantibodies in SLE patients in the four clusters. P value represent difference in
SSA/SSB autoantibody status between clusters of SLE patients, uncorrected p value is presented (Bonferroni corrected threshold p=0.002).
variants, with an average number of around 32 variants per indi- mucin in mucus (table 3). Five patients with SLE carried the
vidual for both patients with SLE and control individuals (online same deleterious MUC5B missense mutation (rs773068050,
supplemental figure S6). None of the patients with SLE were p.Thr2724Pro). MUC5B gene variants have previously been asso-
homozygous carriers of rare non-synonymous alleles in genes ciated with interstitial lung disease (ILD), a condition affecting
for monogenic SLE and lupus-like diseases (online supplemental around 3% of Swedish patients with SLE.29–31 However, there
table S10). Next, we hypothesised that protein coding variants was no evidence of ILD in these five patients, but two of them
observed exclusively in patients with SLE could be causal candi- had suffered from pleuritis (online supplemental table S12). In
dates. A total of 1475 case-only nonsynonymous variants were conclusion, we did not find evidence for SLE patients carrying a
identified in the 958 patients with SLE (online supplemental generally increased burden of rare coding variants at these genes.
table S11). These were variants that were observed in at least However, our analysis identified a number of coding variants
one patient with SLE, but not in control individuals of similar observed exclusively in patients with SLE. This catalogue of vari-
ancestry.27 28 The most frequent of these SNVs was found in the ants could serve as a resource for future studies investigating the
MUC5B gene which encodes mucin 5B, the major gel-forming role of case-only SNVs in SLE.
Figure 4 Clustering of patients with SLE based on pathway Polygenic Risk Scores (PRS). Heat map with pathways on the x-axis (KEGG IDs) and
individuals on the y-axis based on normalised PRS. Hierarchical cluster analysis was performed based on the PRS per pathway for each individual. The
colour bar on the left indicates the four main clusters of individuals identified. KEGG, Kyoto Encyclopaedia of Genes and Genomes; SLE, systemic lupus
erythematosus.
Table 2 Gene-set analyses of SLE-associated genes and involved pathways
Set name Genes tested No of SNVs all/common/rare FDRALL FDRCOMMON FDRRARE
Interferon (ref 21) 33 4204/849/2866 0.0018 0.66 0.65
Interferonopathy (ref 22,23) 11 2034/463/1271 0.0028 4.1E-07 0.24
SLE GWAS (ref 3,4) 88 18790/5326/11465 1.5E-12 2.0E-15 0.18
Complement* 32 4712/1094/3086 0.00071 2.8E-07 0.20
Monogenic SLE (ref 24) 24 3745/930/2371 2.9E-07 2.9E-11 0.020
All: including all MAFs; Common: MAF >0.05; Rare: MAF <0.01.
*The complement part of KEGG pathway hsa04610.
FDR, false discovery rate; GWAS, genome-wide association study; KEGG, kyoto encyclopedia of genes and genomes; MAF, minor allele frequency; SLE, systemic lupus
erythematosus; SNV, single-nucleotide variant.
DISCUSSION option in a subset of patients with SLE.34 Conversely, low-dose

We here suggest a novel pathway- based approach to stratify IL-2 treatment in SLE to stimulate T regulatory cells has recently
patients with SLE beyond clinical manifestations. Further, we shown promising results.35
characterise genetic pathway associations and investigate rare We observed that the T cell differentiation pathway associ-
variant contributions to the pathogenesis of SLE, all using ations were influenced by genetic associations to HLA, which
targeted sequencing of immunity genes. is not surprising given the essential role of HLA in the immune
Using case–control association testing for immunological response. This was further demonstrated by the antigen
pathways, we identified two main axes of SLE association: T processing and presentation pathway association dominated by
cell differentiation and innate immunity pathways. T cells have a HLA genes. Complement pathway associations are also possibly
fundamental role in loss of tolerance, autoimmunity and inflam- confounded by the HLA SLE association, since early comple-
matory reactions. In SLE, a number of different T cell disturbances ment component genes are located in the HLA class III locus on
have been described, which can contribute to the generation of chromosome 6.36 The JAK-STAT pathway was associated with
autoreactive T cells, aberrant cytokine production and impaired SLE, it is the main route to initiate gene expression and protein
T regulatory cell function.32 Besides the direct involvement of synthesis for over 50 cytokines, many of which are involved in
pathways connected to Th1 and Th2 cells, we noticed associa- the SLE disease process.37 38 Variants of a number of genes in the
tion signals from two pathways related to interleukin 17 (IL-17). JAK-STAT pathway have been associated with an increased risk
A proportion of patients with SLE display raised serum levels for SLE, for instance STAT4-STAT1 and TYK2.3 4
of IL-17, elevated numbers of circulating IL-17- producing T Our study highlights the importance of the interferon system
cells and increased IL-17 production by lymphocytes, suggesting in SLE. Previous studies have shown genetic associations at a
dysregulation of T regulatory cells.33 Our findings strengthen the number of genes in the IFN signalling pathway in SLE.2 3 Here,
recent suggestions that IL-17 inhibition could be a therapeutic we show that, in aggregate, genetic variation at interferonopathy
Table 3 SLE case-only recurrent non-synonymous SNVs

Amino acid
CHR BP SNV Ref allele Alt allele Count SLE Gene Consequence change SIFT
11 1 266 280 rs773068050 A C 5 MUC5B Missense variant p.Thr2727Pro Deleterious(0.05)
1 186 363 103 rs1292231132 C A 4 C1orf27 Missense variant p.Gln246Lys Tolerated(0.21)
1 151 342 270 rs772030489 G T 2 SELENBP1 Missense variant p.Pro36Thr Deleterious low
confidence(0.01)
2 27 455 971 rs776014297 T A 2 CAD Missense variant p.Met922Lys Deleterious(0.04)
2 179 698 928 rs892049188 G A 2 CCDC141 Missense variant p.Ser1522Phe Tolerated(0.08)
9 16 431 447 chr9:16 431 447 G A 2 BNC2 Missense variant p.His307Tyr –
9 21 166 175 rs779242420 T C 2 IFNA21 Missense variant p.Tyr146Cys Deleterious(0.01)
10 75 583 821 chr10:75 583 821 G T 2 CAMK2G Missense variant p.His370Asn Deleterious low
confidence(0.03)
12 6 458 353 rs775543049 G A 2 SCNN1A Stop gained p.Arg551* –
12 48 482 728 rs750735162 T C 2 SENP1 Missense variant p.Thr155Ala Deleterious low
confidence(0)
12 56 350 882 rs1425141530 G T 2 PMEL Missense variant p.Pro402His Deleterious(0.02)
12 129 190 793 rs1386045604 C G 2 TMEM132C Missense variant p.Pro1094Ala Tolerated(0.21)
14 23 057 866 chr14:23 057 866 A T 2 DAD1 Missense variant p.Ser66Arg Deleterious(0.04)
15 91 030 272 rs181919733 G A 2 IQGAP1 Missense variant p.Val1371Met Tolerated(0.07)
17 41 143 320 rs1456586259 G A 2 RUNDC1 Missense variant p.Val477Ile Tolerated(0.12)
19 4 891 395 rs139019426 T C 2 ARRDC5 Missense variant p.Gln231Arg Tolerated(0.86)
19 18 273 781 rs777121279 G A 2 PIK3R2 Missense variant p.Gly372Ser Deleterious(0)
19 55 240 959 rs764066889 G A 2 KIR3DL3 Missense variant, p.Gly219Asp Deleterious(0.02)
splice region variant
SIFT (Sorting Intolerant From Tolerant) prediction whether the amino acid substitution affects protein function.
BP, base pair; CHR, chromosome; SLE, systemic lupus erythematosus; SNV, single-nucleotide variant.

2
genes also contribute to risk for SLE. In addition to interferonop- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology,
athy genes, we also observed an aggregate genetic association for Uppsala University, Uppsala, Sweden
3
Department of Psychiatry, Washington University, St. Louis, Missouri, USA
monogenic SLE and lupus-like disease genes with both a rare and 4
Division of Rheumatology, Department of Medicine, Karolinska Institutet and
a common variant contribution. This supports the hypothesis of a Karolinska University Hospital, Stockholm, Sweden
5
shared genetic basis and consequently disease mechanisms between Department of Public Health and Clinical Medicine/Rheumatology, Umeå University,
monogenic and complex forms of disease, where also common Umeå, Sweden
6
Broegelmann Research Laboratory, Department of Clinical Science, University of
non-coding variants can affect the regulation of Mendelian disease Bergen, Bergen, Norway
genes resulting in clinically similar traits.39 7
Clinical Immunology unit, Department of Internal Medicine, Stavanger University
We have previously demonstrated that an SLE genetic risk score Hospital, Stavanger, Norway
8
was associated with disease severity in SLE.5 We here generated a Department of Medical Genetics, University of Oslo, Oslo, Norway
9
Institute for Inflammation Research, Center for Rheumatology and Spine Diseases,
pathway-centred SLE PRS and found that there was a large variation Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
in the number of affected pathways among the patients, which under- 10
Department of Clinical Immunology, Aalborg University, Aalborg, Denmark
11
scores the heterogeneity of SLE. We observed higher SLE damage Department of Clinical Immunology, Odense University Hospital, Odense, Denmark
12
indexes in patients with SLE positive for the B or T cell receptor Department of Rheumatology, Oslo University Hospital, Oslo, Norway
13
Institute of Clinical Medicine, University of Oslo, Oslo, Norway
signalling pathways, thus, pathways in the adaptive immune system 14
Department of Rheumatology, Odense University Hospital, Odense, Denmark
seem important for the long-term severity of the disease. This is in 15
Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
16
accordance with previous findings that SLE disease activity correlates Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
17
with abnormal B lymphocyte activity and T cell abnormalities, as Center for Rheumatology and Spine Diseases, Copenhagen University Hospital
Rigshospitalet, Copenhagen, Denmark
well as the connection between disease activity and accumulation of 18
Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
organ damage.40 41 19
Department of Medical Sciences, Molecular Medicine and Science for Life
We attempted to cluster patients into subsets with shared Laboratory, Uppsala University, Uppsala, Sweden
20
genetic pathway profiles, which suggested four subgroups of Department of Clinical Sciences Lund, Rheumatology, Lund University, Skane
University Hospital, Lund, Sweden
patients with SLE. Beside the SSA/SSB antibody profile, these 21
Department of Biomedical and Clinical Sciences, Division of Inflammation and
clusters were not connected to clinical disease manifestations Infection, Linköping University, Linköping, Sweden
22
such as nephritis or survival. This observation may indicate that Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
the PRS reflects part of the central autoimmune process, which Acknowledgements DNA sequencing and genotyping was performed at the
is not translated into specific organ manifestations. Whether the SNP&SEQ Technology Platform in Uppsala. The facility is part of the National
PRS in individual patients with SLE, or the different clusters, Genomics Infrastructure (NGI) Sweden and Science for Life Laboratory. Computations
were performed on resources provided by the Swedish National Infrastructure
contribute to treatment response is an interesting possibility, but for Computing (SNIC) through Uppsala Multidisciplinary Centre for Advanced
could not be assessed in this study. This is one limitation of our Computational Science (UPPMAX) under projects SNIC SENS 2017142 and
study, together with the fact that our conclusions apply specifi- 2017107. The SweGen genotype data were generated by Science for Life Laboratory.
cally to this set of candidate genes. The authors would like to thank the Genome Aggregation Database (gnomAD)
and the groups that provided exome and genome variant data to this resource. A
WGS or WES studies will be required to fully elucidate the role of full list of contributing groups can be found at the gnomAD website. The authors
rare variants and pathways in SLE. As previously shown by us and wish to thank the Uppsala Bioresource Karolina Tandre and Västerbotten biobank
others, WGS and WES in selected patients can provide information for providing DNA samples on control individuals, and Cane Amcoff for excellent
on ultrarare and de novo SNVs in SLE.6 7 42 However, larger sample technical assistance.
sizes than those reported to date will be required to paint a complete Collaborators The DISSECT consortium: Johanna K. Sandling (Department of
picture of the genetic aetiology of SLE. We did not find support Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden), Pascal
Pucholt (Department of Medical Sciences, Rheumatology, Uppsala University,
in additional Scandinavian cohorts for a role in SLE for the novel Sweden), Lina Hultin Rosenberg (Science for Life Laboratory, Department of Medical
loci identified in the Swedish cohorts. Possible explanations include Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden), Fabiana
overestimated effect sizes in the discovery cohort, differences in H.G. Farias (Science for Life Laboratory, Department of Medical Biochemistry and
genetic background within Scandinavia, or differences in clinical Microbiology, Uppsala University, Uppsala, Sweden, and Department of Psychiatry,
Washington University, St. Louis, MO, USA), Sergey V. Kozyrev (Science for Life
manifestations or characterisation of patients. Lastly, our study iden- Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala
tified a large number of case-only coding variants. Variants uniquely University, Uppsala, Sweden), Maija-Leena Eloranta (Department of Medical
identified in patients could be causal candidates in SLE, but their Sciences, Rheumatology, Uppsala University, Uppsala, Sweden), Andrei Alexsson
statistical significance is difficult to evaluate. (Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala,
Sweden), Matteo Bianchi (Science for Life Laboratory, Department of Medical
In summary, we have suggested a novel strategy to genetically Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden), Leonid
stratify patients with SLE according to involved molecular pathways. Padyukov (Division of Rheumatology, Department of Medicine, Karolinska Institutet
T cell pathways displayed the strongest association, which highlights and Karolinska University Hospital, Stockholm, Sweden), Christine Bengtsson
the importance of the adaptive immune system in the disease. The (Department of Public Health and Clinical Medicine/Rheumatology, Umeå University,
Umeå, Sweden), Roland Jonsson (Broegelmann Research Laboratory, Department
strong connection to the JAK-STAT pathway, including the IFN of Clinical Science, University of Bergen, Bergen, Norway), Roald Omdal (Clinical
system, is perhaps not surprising given the promising clinical trials Immunology unit, Department of Internal Medicine, Stavanger University Hospital,
of JAK and type I interferon receptor inhibition as treatments for Stavanger, Norway and Broegelmann Research Laboratory, Department of Clinical
SLE.38 43 44 However, not all patients in these studies respond to Science, University of Bergen, Bergen, Norway), Øyvind Molberg (Department of
Rheumatology, Oslo University Hospital and Institute of Clinical Medicine, University
treatment, and dissecting affected molecular pathways in responders of Oslo, Oslo, Norway), Ann-Christine Syvänen (Department of Medical Sciences,
and non-responders could increase the understanding of treatment Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala,
outcome. This approach has not been tested clinically, but the future Sweden), Andreas Jönsen (Lund University, Skane University Hospital, Department
of precision medicine for SLE lies in identifying robust methods to of Clinical Sciences Lund, Rheumatology, Lund, Sweden), Iva Gunnarsson (Division
of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska
perform molecular stratification of patients. University Hospital, Stockholm, Sweden), Elisabet Svenungsson (Division of
Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska
Author affiliations University Hospital, Stockholm, Sweden), Solbritt Rantapää-Dahlqvist (Department
1
Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå,
Sweden Sweden), Anders A. Bengtsson (Lund University, Skane University Hospital,

Department of Clinical Sciences Lund, Rheumatology, Lund, Sweden), Christopher Ethics approval The study was approved by the regional ethics board in Uppsala
Sjöwall (Department of Biomedical and Clinical Sciences, Division of Inflammation (Dnr 2015/450 and 2016/155).
and Infection, Linköping University, Linköping, Sweden), Dag Leonard (Department Provenance and peer review Not commissioned; externally peer reviewed.
of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden), Kerstin
Lindblad-Toh (Science for Life Laboratory, Department of Medical Biochemistry Data availability statement The datasets generated and/or analysed during
and Microbiology, Uppsala University, Uppsala, Sweden and Broad Institute of the current study are not publicly available due to them containing information that
MIT and Harvard, Cambridge, MA, USA), Lars Rönnblom (Department of Medical could compromise research participant privacy and consent, but are available from
Sciences, Rheumatology, Uppsala University, Uppsala, Sweden), Jonas Carlsson the corresponding authors LR (ORCID 0000-0001-9403-6503) and JKS (ORCID
Almlöf (Department of Medical Sciences, Molecular Medicine and Science for Life 0000-0003-1382-2321) on reasonable request and on a collaborative basis.
Laboratory, Uppsala University, Uppsala, Sweden), Johanna Dahlqvist (Science Supplemental material This content has been supplied by the author(s). It
for Life Laboratory, Department of Medical Sciences and Department of Medical has not been vetted by BMJ Publishing Group Limited (BMJ) and may not
Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden), Daniel have been peer-reviewed. Any opinions or recommendations discussed are
Eriksson (Department of Medicine (Solna), Karolinska Institutet, and Department of solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all
Endocrinology, Metabolism and Diabetes Karolinska University Hospital, Stockholm, liability and responsibility arising from any reliance placed on the content.
Sweden), Niklas Hagberg (Department of Medical Sciences, Rheumatology, Uppsala Where the content includes any translated material, BMJ does not warrant the
University, Uppsala, Sweden), Ingrid E. Lundberg (Division of Rheumatology, accuracy and reliability of the translations (including but not limited to local
Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, regulations, clinical guidelines, terminology, drug names and drug dosages), and
Stockholm, Sweden), Argyri Mathioudaki (Science for Life Laboratory, Department is not responsible for any error and/or omissions arising from translation and
of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden), adaptation or otherwise.
Jennifer Meadows (Science for Life Laboratory, Department of Medical Biochemistry
and Microbiology, Uppsala University, Uppsala, Sweden), Jessika Nordin (Science Open access This is an open access article distributed in accordance with the
for Life Laboratory, Department of Medical Biochemistry and Microbiology, Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits
Uppsala University, Uppsala, Sweden), Gunnel Nordmark (Department of Medical others to copy, redistribute, remix, transform and build upon this work for any
Sciences, Rheumatology, Uppsala University, Uppsala, Sweden), Marie Wahren- purpose, provided the original work is properly cited, a link to the licence is given,
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Karolinska University Hospital, Stockholm, Sweden and Broegelmann Research licenses/by/4.0/.
Laboratory, Department of Clinical Science, University of Bergen, Norway), Sule
ORCID iDs
Yavuz (Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala,
Johanna K Sandling http://orcid.org/0000-0003-1382-2321
Sweden). The ImmunoArray development consortium: Kerstin Lindblad-Toh (Science
Pascal Pucholt http://orcid.org/0000-0003-3342-1373
for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala
Elisabet Svenungsson http://orcid.org/0000-0003-3396-3244
University, Uppsala, Sweden and Broad Institute of MIT and Harvard, Cambridge,
Christopher Sjöwall http://orcid.org/0000-0003-0900-2048
MA, USA), Gerli Rosengren Pielberg (Science for Life Laboratory, Department of
Lars Rönnblom http://orcid.org/0000-0001-9403-6503
Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden), Anna
Lobell (Office for Medicine and Pharmacy, Uppsala University, Uppsala, Sweden),
REFERENCES
Åsa Karlsson (Science for Life Laboratory, Department of Medical Biochemistry
1 Bengtsson AA, Rönnblom L. Systemic lupus erythematosus: still a challenge for
and Microbiology, Uppsala University, Uppsala, Sweden), Eva Murén (Science for
physicians. J Intern Med 2017;281:52–64.
Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala
2 Crow MK, Ronnblom L. Type I interferons in host defence and inflammatory diseases.
University, Uppsala, Sweden), Göran Andersson (Department of Animal Breeding and
Lupus Sci Med 2019;6:e000336.
Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden), Kerstin M.
3 Chen L, Morris DL, Vyse TJ. Genetic advances in systemic lupus erythematosus: an
Ahlgren (Department of Surgical Sciences, Uppsala University, Uppsala, Sweden),
update. Curr Opin Rheumatol 2017;29:423–33.
Lars Rönnblom (Department of Medical Sciences, Rheumatology, Uppsala University,
4 Langefeld CD, Ainsworth HC, Cunninghame Graham DS, et al. Transancestral mapping
Uppsala, Sweden), Maija-Leena Eloranta (Department of Medical Sciences, and genetic load in systemic lupus erythematosus. Nat Commun 2017;8:16021.
Rheumatology, Uppsala University, Uppsala, Sweden), Nils Landegren (Department 5 Reid S, Alexsson A, Frodlund M, et al. High genetic risk score is associated with
of Medicine (Solna), Center for Molecular Medicine, Karolinska Institutet, Stockholm, early disease onset, damage accrual and decreased survival in systemic lupus
Sweden and Science for Life Laboratory, Department of Medical Sciences, Uppsala erythematosus. Ann Rheum Dis 2020;79:363–9.
University, Uppsala, Sweden), Olle Kämpe (Department of Medicine (Solna), Center 6 Pullabhatla V, Roberts AL, Lewis MJ, et al. De novo mutations implicate novel genes in
for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden, Department of systemic lupus erythematosus. Hum Mol Genet 2018;27:421–9.
Endocrinology, Metabolism and Diabetes Karolinska University Hospital, Stockholm, 7 Almlöf JC, Nystedt S, Leonard D, et al. Whole-genome sequencing identifies complex
Sweden, Science for Life Laboratory, Department of Medical Sciences, Uppsala contributions to genetic risk by variants in genes causing monogenic systemic lupus
University, Uppsala, Sweden and KG Jebsen Center for autoimmune diseases, erythematosus. Hum Genet 2019;138:141–50.
University of Bergen, Norway), Peter Söderkvist (Division of Cell Biology, Department 8 Jiang SH, Athanasopoulos V, Ellyard JI, et al. Functional rare and low frequency
of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden). variants in BLK and BANK1 contribute to human lupus. Nat Commun 2019;10:2201.
Contributors KLT and LR conceived and designed the experiments. CB, KL, AV, 9 Wang Y, Chen S, Chen J, et al. Germline genetic patterns underlying familial
AMT, SJ, AJ, IG, ES, SR-D, AAB, CS and DL characterised the patient samples. M-LE, rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren’s syndrome
LP, LM, RS, MAJ, RJ, RO, BAL and STL provided samples and data. The ImmunoArray highlight T cell-initiated autoimmunity. Ann Rheum Dis 2020;79:268–75.
development consortium members designed the targeted sequencing panel. FHGF, 10 Raj P, Rai E, Song R, et al. Regulatory polymorphisms modulate the expression of HLA
SVK, ÅK, and EM performed the experiments. A-CS managed the sequencing class II molecules and promote autoimmunity. Elife 2016;5. doi:10.7554/eLife.12089.
platform. JKS, LHR, PP, AA and MB analysed the data and the DISSECT consortium [Epub ahead of print: 15 Feb 2016].
members provided intellectual input and/or developed analysis pipelines. JKS and 11 Richardson TG, Timpson NJ, Campbell C, et al. A pathway-centric approach to rare
LR wrote the manuscript. All authors read, provided critical review and accepted the variant association analysis. Eur J Hum Genet 2016;25:123–9.
final version of the manuscript. 12 Banchereau R, Hong S, Cantarel B, et al. Personalized Immunomonitoring uncovers
molecular networks that stratify lupus patients. Cell 2016;165:551–65.
Funding This study was supported by an AstraZeneca-Science for Life Laboratory
13 El-Sherbiny YM, Psarras A, Md Yusof MY, et al. A novel two-score system for interferon
Research Collaboration grant (DISSECT). This study was also supported by grants
status segregates autoimmune diseases and correlates with clinical features. Sci Rep
from the Swedish Research Council for Medicine and Health (Dnr 2018–02399,
2018;8:5793.
2018–02535 and a Distinguished professor award to KL-T), the Swedish
14 Guthridge JM, Lu R, Tran LT-H, et al. Adults with systemic lupus exhibit distinct
Rheumatism Association, King Gustav V’s 80-year Foundation, the Swedish-Heart- molecular phenotypes in a cross-sectional study. EClinicalMedicine 2020;20:100291.
Lung foundation, a Wallenberg Scholar Award (to KL-T), and the Swedish Society of 15 Lindblad-Toh K, Garber M, Zuk O, et al. A high-resolution map of human evolutionary
Medicine and the Ingegerd Johansson donation. The SNP&SEQ Platform is supported constraint using 29 mammals. Nature 2011;478:476–82.
by Science for Life Laboratory, the Swedish Research Council (VR-RFI), Uppsala 16 Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of
University and the Knut and Alice Wallenberg Foundation. systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7.
Disclaimer The funders had no role in the design of the study or collection, 17 Hochberg MC. Updating the American College of rheumatology revised criteria for the
analysis, or interpretation of data or in writing the manuscript. classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725.
18 Eriksson D, Bianchi M, Landegren N, et al. Extended exome sequencing identifies BACH2 as
Competing interests An AstraZeneca research collaboration grant to LR
a novel major risk locus for Addison’s disease. J Intern Med 2016;280:595–608.
supported the study. LHR is now an employee of Olink Proteomics.
19 Li JZ, Absher DM, Tang H, et al. Worldwide human relationships inferred from
Patient consent for publication Not required. genome-wide patterns of variation. Science 2008;319:1100–4.

20 Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids 33 Krebs CF, Schmidt T, Riedel J-H, et al. T helper type 17 cells in immune-mediated
Res 2000;28:27–30. glomerular disease. Nat Rev Nephrol 2017;13:647–59.
21 Rönnblom L, Leonard D. Interferon pathway in SLE: one key to unlocking the mystery 34 Koga T, Ichinose K, Kawakami A, et al. The role of IL-17 in systemic lupus
of the disease. Lupus Sci Med 2019;6:e000270. erythematosus and its potential as a therapeutic target. Expert Rev Clin Immunol
22 Rodero MP, Crow YJ. Type I interferon-mediated monogenic autoinflammation: the 2019;15:629–37.
type I interferonopathies, a conceptual overview. J Exp Med 2016;213:2527–38. 35 He J, Zhang R, Shao M, et al. Efficacy and safety of low-dose IL-2 in the treatment of
23 Davidson S, Steiner A, Harapas CR, et al. An update on autoinflammatory diseases: systemic lupus erythematosus: a randomised, double-blind, placebo-controlled trial.
Interferonopathies. Curr Rheumatol Rep 2018;20:38. Ann Rheum Dis 2020;79:141–9.
24 Tsokos GC, Lo MS, Costa Reis P, et al. New insights into the immunopathogenesis of 36 Kamitaki N, Sekar A, Handsaker RE, et al. Complement genes contribute sex-biased
systemic lupus erythematosus. Nat Rev Rheumatol 2016;12:716–30. vulnerability in diverse disorders. Nature 2020;582:577–81.
25 Lee S, Emond MJ, Bamshad MJ, et al. Optimal unified approach for rare-variant 37 Villarino AV, Kanno Y, O’Shea JJ. Mechanisms and consequences of Jak-STAT signaling
association testing with application to small-sample case-control whole-exome in the immune system. Nat Immunol 2017;18:374–84.
sequencing studies. Am J Hum Genet 2012;91:224–37. 38 Alunno A, Padjen I, Fanouriakis A, et al. Pathogenic and therapeutic relevance of JAK/
26 Mossotto E, Ashton JJ, O’Gorman L, et al. GenePy - a score for estimating STAT signaling in systemic lupus erythematosus: integration of distinct inflammatory
pathways and the prospect of their inhibition with an oral agent. Cells 2019;8.
gene pathogenicity in individuals using next-generation sequencing data. BMC
doi:10.3390/cells8080898. [Epub ahead of print: 15 Aug 2019].
Bioinformatics 2019;20:254.
39 Freund MK, Burch KS, Shi H, et al. Phenotype-Specific enrichment of Mendelian
27 Ameur A, Dahlberg J, Olason P, et al. SweGen: a whole-genome data resource of
disorder genes near GWAS regions across 62 complex traits. Am J Hum Genet
genetic variability in a cross-section of the Swedish population. Eur J Hum Genet
2018;103:535–52.
2017;25:1253–60.
40 Li W, Deng C, Yang H, et al. The regulatory T cell in active systemic lupus
28 Karczewski KJ, Francioli LC, Tiao G, et al. Variation across 141456 human exomes and erythematosus patients: a systemic review and meta-analysis. Front Immunol
genomes reveals the spectrum of loss-of-function intolerance across human protein- 2019;10:159.
coding genes. bioRxiv 2019:531210. 41 Nossent J, Cikes N, Kiss E, et al. Current causes of death in systemic lupus
29 Frodlund M, Reid S, Wetterö J, et al. The majority of Swedish systemic lupus erythematosus in Europe, 2000--2004: relation to disease activity and damage
erythematosus patients are still affected by irreversible organ impairment: factors accrual. Lupus 2007;16:309–17.
related to damage accrual in two regional cohorts. Lupus 2019;28:1261–72. 42 Almlöf JC, Nystedt S, Mechtidou A, et al. Contributions of de novo variants to systemic
30 Hunninghake GM, Hatabu H, Okajima Y, et al. MUC5B promoter polymorphism and lupus erythematosus. Eur J Hum Genet 2020. doi:10.1038/s41431-020-0698-5.
interstitial lung abnormalities. N Engl J Med 2013;368:2192–200. [Epub ahead of print: 28 Jul 2020].
31 Namba N, Kawasaki A, Sada K-E, et al. Association of MUC5B promoter 43 Wallace DJ, Furie RA, Tanaka Y, et al. Baricitinib for systemic lupus erythematosus:
polymorphism with interstitial lung disease in myeloperoxidase-antineutrophil a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet
cytoplasmic antibody-associated vasculitis. Ann Rheum Dis 2019;78:1144–6. 2018;392:222–31.
32 Crispin JC, Hedrich CM, Suárez-Fueyo A, et al. SLE-Associated defects promote altered 44 Morand EF, Furie R, Tanaka Y, et al. Trial of Anifrolumab in active systemic lupus
T cell function. Crit Rev Immunol 2017;37:39–58. erythematosus. N Engl J Med 2020;382:211–21.

BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis
MOLECULAR PATHWAYS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS REVEALED BY

GENE CENTRED DNA SEQUENCING
Sandling et al.
Contents:
Supplementary Materials and Methods
Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

Supplementary Materials and Methods
Subjects and DNA samples
The Swedish SLE cohorts included 1,167 SLE patients recruited at the Rheumatology clinics at the
Uppsala, Karolinska (Solna), Umeå, Lund and Linköping University Hospitals. Blood samples and
clinical information originated from time of diagnosis, study inclusion or follow-up visits, and clinical
information was compiled at the end of follow-up. An extended follow-up was performed specifically
for death as outcome. The controls were healthy blood donors or population controls from Uppsala
Bioresource and Västerbotten biobank in Sweden (n=1,101). Genomic DNA extracted from blood
samples was available for genetic analysis. DNA samples for sequencing were selected based on DNA
amount and quality if multiple DNA samples were available for the same individual. The quality-
controlled dataset used in subsequent analyses contained 958 SLE patients and 1,026 control
individuals. All 958 SLE patients fulfilled at least four of the classification criteria for SLE as defined by
the American College of Rheumatology (ACR).(1, 2) Renal biopsies were classified according to the
WHO or the ISN/RPS 2003 classification systems.(3) Clinical characteristics of the patients are
available in online supplementary Tables S1a and S1b. All subjects provided informed consent to
participate in the study, and the study was approved by the regional ethics board in Uppsala (Dnr
2015/450 and 2016/155).
Targeted DNA sequencing
Targeted DNA sequencing was performed in the Swedish SLE case-control cohorts. The design of the
sequence capture panel and the library preparation has been described elsewhere.(4) In brief, a
custom SeqCap EZ Choice XL library (Roche NimbleGen, Basel, Switzerland) was designed to target
1,853 genes, selected based on their known or suspected roles in immunological or autoimmune
diseases in humans or model organisms.(4) The genomic intervals for all alternative transcripts were
retrieved from NCBI36/hg18. Besides the coding exons, 5′ and 3′ UTRs, potential promoter regions
(±2 kb from transcription start sites) and splice sites (±20 bp of intronic sequences adjacent to exons)

were also included, as well as regions of mammalian conservation within 100kb up- and downstream
of the genes.(5) In total, the designed probes covered 32.3 Mbp. Sequencing libraries were prepared
by ultrasonication of up to 1 μg of high molecular weight DNA into around 400 bp fragments (Covaris
E220, Woburn, MA, USA), that were then barcoded (NEXTflex-96 DNA barcode adapters, Bioo
Scientific, Austin, TX, USA). Samples were pooled in batches of eight, hybridized (Roche NimbleGen)
and sequenced with 100-bp paired-end reads using Illumina HiSeq 2500 version 3 or 4 chemistry
(Illumina Inc, San Diego, CA, USA). An average sequencing depth of 35× per sample was achieved.
Alignment and variant calling
A pipeline based on GATK “best practices” was used for variant discovery.(6) Raw reads were
mapped to the hg19 human reference genome using the Burrows-Wheeler aligner 0.7.12 (7) and
duplicate reads marked by Picard 1.92. GATK 3.3.0 was applied for realignment around indels, base
quality score recalibration, SNP and indel discovery and joint genotyping. Prior to genotyping,
alignment quality was evaluated by Samtools flagstat (7) and Picard tools CalculateHSMetrics and
samples with mean target coverage less than 10x were excluded. From this point on, only bi-allelic
single nucleotide variants (SNVs) were considered. SNV quality scores were recalibrated using GATK
3.3.0 VariantRecalibrator and filtered at tranche level 99.0. Using VCFtools,(8) genotype calls with
depth less than 8 reads and genotype Phred quality score less than 20 were excluded.(9)
Sample and variant level quality control
Study population genetic structure was analysed by the LASER software using default parameters and
the Human Genome Diversity Project (HGDP) as reference population (online supplementary Figure
S7a).(10, 11) Population outliers were defined using the following criteria: 1) study subjects falling
more than five standard deviations outside of the mean of the European sub-population of the HGDP
reference set were excluded, 2) mean and standard deviation were calculated for the remaining
study subjects and any additional subjects falling more than five standard deviations outside of the

study mean were excluded, 3) step 2 was repeated until no additional subjects were excluded.
Relatedness among study subjects was determined using the KING software, applying default
thresholds for duplicate and first degree relationships.(12) Extreme sample outliers were identified
based on several quality control (QC) measures, as suggested by Do et al.(13) These QC parameters
included rate of missing data, heterozygosity ratio, transition-transversion ratio and singleton counts.
Further, samples were excluded if they exhibited discordance between reported sex and that
inferred from sequence data or if they exhibited discordance between genotypes inferred from
sequence data and a genotype dataset from a previous study.(14) Lastly, it was required that samples
had a minimum call rate of 80%.
A number of filters were applied to exclude low quality variants. Heterozygous calls were included
only if their allelic balance across all samples was between 0.2 and 0.8. Positions deviating from
Hardy-Weinberg equilibrium (P <1x10-6, calculated on controls) were excluded as well as
monomorphic sites. Finally, a minimum of 90% variant call rate was required. The remaining variant
positions were investigated for differential missingness between cases and controls using PLINK (15),
and significantly different variants were excluded (P <0.05 Bonferroni corrected). An overview of the
QC steps can be found in online supplementary Figure S1. The quality-controlled dataset used in
subsequent analyses contained 958 Swedish SLE patients, 1,026 control individuals, 287,354 SNVs
and covered 1,832 of the targeted gene regions. The average individual call rate was 98.2% and the
average variant call rate 98.2%. Genotypes from targeted sequencing were validated using an
independent genotype array dataset (Illumina ImmunoChip) on an overlapping set of 1,693 Swedish
individuals and 8,483 SNVs after QC.(14) SNV genotype concordance was on average 99.8% (online
supplementary Figure S8).
Variant level annotation
Variant annotation was performed using SnpEff v4.2.(16) Non-synonymous variants were defined as
SNVs annotated as missense or nonsense variants. Non-coding SNVs were defined as SNVs annotated

to upstream, downstream, intergenic regions or regions overlapping transcription factor binding
sites, but not as missense or nonsense SNVs. The extended HLA region spanning a region of 7.9 Mbp
was defined as from the gene SCGN to SYNGAP1 on hg19 chr6:25,652,429-33,560,852.(17)
Evolutionarily constrained positions were defined as having a Genomic Evolutionary Rate Profiling
(GERP) rejected substitutions (RS) score >2.(18) In analyses of rare SNVs, variants with MAFs <0.01
were included, and for common SNVs variants with MAFs ≥0.05 were included.
Single variant analyses
Principal components for population stratification were generated in EIGENSOFT (19) after excluding
long-range linkage disequilibrium (LD) regions (20), SNVs with MAF<0.05 and SNVs in LD r2>0.2
(online supplementary Figure S7b-d). Single variant association analyses for variants with MAF≥0.01
were performed in PLINK using a logistic regression model, in which the three first principal
components were added as regression covariates. Two levels of significance were applied, an
experiment-wide P-value threshold of 1.8 x10-6 (P < 0.05 Bonferroni corrected, limiting LD to r2<0.2
which resulted in 27,195 variants used for multiple testing correction) and a suggestive threshold of
P<1x10-4. LD was measured by r2 calculated in PLINK. Manhattan and QQ plots were generated in R
using the package qqman.(21, 22) Regional plots of associations were generated using R. Conditional
analysis, using the top SNP from the previous model as covariate, was performed until there were no
residual association signals below the suggestive threshold (P <1x10-4). Differences in variant load
between SLE patients and controls were assessed by the Mann-Whitney U test. SLE case-only
variants were identified by removing all SNVs present in our control dataset of 1,026 individuals, in
the SweGen project 1,000 individuals version September 4th, 2017 generated by Science for Life
Laboratory(23) or in the Genome Aggregation Database (gnomAD) European non-Finnish controls
v2.1.1.(24)

Aggregate association testing
Variant-sets were generated for aggregate association testing using three different strategies. 1)
Gene variant-sets for gene-based association testing: The RefSeq annotation of the hg19 human
genome assembly was used to assign genomic positions to each target gene.(25) Aggregate spaces
were generated such that the minimal transcript start site and the maximal transcript end site of any
transcript for each gene was recorded. The spaces were then extended by 100kb on each end to
include regulatory regions, except in analyses focusing on rare coding variants only. Variants falling
within the same aggregate gene space were assembled into a gene variant set. 2) Pathway variant-
sets for pathway-based association testing: Pathway-wide aggregate spaces were generated by
utilising information from the Kyoto Encyclopedia of Genes and Genomes (KEGG) on membership of
genes in pathways.(26) Pathway spaces were defined as the union of gene spaces of genes annotated
to be part of each pathway. Association testing was performed only for pathways that were
represented by at least five genes in the sequencing data, and where at least 50% of the genes in the
pathway were targeted. Additionally, the Human Diseases class of pathways were excluded. This
resulted in 35 KEGG pathway variant-sets for association testing. 3) Literature review gene sets for
gene set-based association testing: the type I interferon pathway (27), interferonopathy genes (28,
29), gene variant sets for SLE GWAS genes (14, 30), the complement subset of the Complement and
coagulation cascades pathway (KEGG hsa04610) and genes causing monogenic SLE or lupus-like
disease (31) were grouped into separate gene sets.
Aggregate association testing was performed separately for each variant-set using SKAT-O with the
inclusion of the first three principal components generated in EIGENSOFT as covariates.(32) We
employed a weighted linear kernel using the default weights as calculated internally by the beta
distribution with parameters a=1 and b=25, giving higher weight to rare variants. To ensure
reproducible outcomes we set the random number seed value in R to 1,337 before running SKAT-O.
For P-value calculation we used the “hybrid” approach that selects the optimal method based on the

total minor allele count (MAC), the number of individuals with minor alleles (m), and the degree of
case-control imbalance. This corrects for conservative type I errors when using a small sample size.
FDR were controlled separately for the pathway, gene-set and gene-based SKAT-O aggregate
association analyses.
Gene-based aggregate association testing including variant deleteriousness metrics was performed
with GenePy.(33) Region annotation and the gene space was dictated by Annovar.(34) GenePy was
run with default parameters, using as reference allele frequencies those in the non-Finnish European
gnomAD v2.1.1 125,748 exomes dataset. The gene annotation was based on RefSeq (RefSeq gene
body + 1Kb upstream and 1Kb downstream). The gene score P-value was obtained by comparing the
distribution of gene scores in cases vs controls using a Mann-Whitney U test. Genes were considered
statistically significant if their P-value was below the permutation P-value. The permutation threshold
was the P-value corresponding to the 5% right tail of the distribution of the lowest P-values obtained
by shuffling the phenotypes (disease status) 1,000 times and running a Mann-Whitney U test. Results
using the REVEL (prediction of the pathogenicity of rare missense variants) and CADD v1.3 (63
annotations, including conservation metrics, functional genomic data, transcript information and
protein level scores) annotations were presented.(35, 36)
Risk scores and cluster analysis
Cumulative pathway SLE polygenic risk scores (pathway PRSs) were assigned to each individual based
on SNVs associated with SLE at nominal significance (P <0.05) in the SLE case-control single variant
association study. The Plink function “clump” was used to remove SNV in high LD (r2 > 0.2) within 250
kbp and to only retain those variants with the highest phenotype association. 1,296 SLE associated
SNVs were retained. Then, for each SNV, the natural logarithm of the OR for SLE susceptibility was
multiplied by the number of minor alleles in each individual. The sum of all products of all genes in
each of the 35 KEGG pathways for each patient was defined as the individual pathway PRS.

Hierarchical cluster analysis with complete linkage on the Euclidean distance between scaled
individual level pathway PRS was used to identify clusters of SLE patients. The NBClust R package was
used to determine the optimal number of clusters by majority voting and four clusters were
determined to be optimal.(37) A heatmap of scaled values of pathway specific PRS was plotted using
the R package ComplexHeatmap.(38) A Chi² test was used to determine if the clusters differed in
composition for case/control status or dichotomous sub phenotypes in SLE patients, while a Mann-
Whitney U test was used to determine if quantitative traits differ between the SLE patients in both
clusters, or if the pathway PRS values differed between SLE cases and healthy controls. Kruskal–
Wallis one-way analysis of variance was used to determine if pathway PRS values differ between
clusters.
Replication study and meta-analysis
The replication study included Norwegian and Danish SLE cohorts recruited at the Oslo University
Hospital, Rigshospitalet in Copenhagen, Odense University Hospital and Aarhus University Hospital.
Only SLE patients fulfilling the ACR SLE classification criteria and of self-reported European ancestry
were included in association analyses. Norwegian and Danish control individuals from the University
Hospitals in Stavanger, Bergen, Odense, Aalborg and Rigshospitalet in Copenhagen were also
included. All subjects provided informed consent to participate in the study, and the study was
approved by the regional ethics boards. 20 SNVs representing association signals at three loci
(CAPN13, IFNK/MOB3B, HAL) or their proxies (LD r2≥0.99) were either genotyped or
extracted/imputed from existing sequencing or GWAS array data.
Genotyping was performed using the iPLEX chemistry on a MassARRAY system (Agena Bioscience,
San Diego, CA, USA). QC included a minimum per sample call rate of 90% and a per variant call rate of
90%. Variants with differential missingness between cases and controls (P <0.01) or Hardy-Weinberg
equilibrium (P <0.01, in controls) were excluded. 836 Norwegian and Danish SLE patients and 782
Danish healthy control individuals passed QC. Quality-controlled genotype data for 143 Norwegian

healthy control individuals was extracted from targeted sequencing data.(39) Replication variants not
called in the sequencing data were imputed with the Sanger imputation service using the Haplotype
reference consortium r1.1 reference dataset and the “pre-phase with EAGLE2 and impute”
pipeline.(40) Imputed genotype calls with genotype probabilities below 0.9 were set to missing and
SNVs with a MAF below 0.01, a Hardy-Weinberg equilibrium P<0.0001, a call rate below 95% or an
imputation probability score below 0.8 were removed, as were individuals with a call rate below
95%.
124 Norwegian control individuals had been genotyped on the Illumina 550 K BeadChip and 298
individuals on the Affymetrix Genome-Wide Human SNP Array 6.0. Hg19 genome assembly genomic
position of variants were assigned based on the rs IDs using the dbSNP version 152 for Illumina or
using the annotation file for Affymetrix. Prior to imputation the datasets were filtered for 95% call
rate both on the variant and individual level, a minimum MAF of 0.05 and a HWE P>1×10-4. Variants
were strand flipped to match the reference allele and variants that could not be resolved were
removed. The resulting datasets were imputed and filtered in the same way as the sequencing-based
dataset described above. After QC the replication dataset included 15 SNVs, 836 SLE patients and
1,211 control individuals.
The Swedish SLE case-control study was expanded to include genotypes from an additional 1,000
control individuals from the SweGen project version September 4th, 2017 generated by Science for
Life Laboratory.(23) Genotypes for proxy variants that were part of the replication study genotyping,
but which were not directly called in the targeted sequencing data, were imputed and quality-
controlled as above. Single variant association analyses were performed separately for the expanded
Swedish, the Norwegian and the Danish case-control studies in PLINK using a logistic regression
model. Meta-analysis of the three association studies results was performed in PLINK assuming a
random effects model. The meta-analysis included a total of 1,794 Scandinavian SLE patients and
3,241 control individuals.

References
1. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of
systemic lupus erythematosus. Arthritis and rheumatism. 1982;25(11):1271-7.
2. Hochberg MC. Updating the American College of Rheumatology revised criteria for the
classification of systemic lupus erythematosus. Arthritis and rheumatism. 1997;40(9):1725.
3. Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in
systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15(2):241-50.
4. Eriksson D, Bianchi M, Landegren N, et al. Extended exome sequencing identifies
BACH2 as a novel major risk locus for Addison's disease. J Intern Med. 2016;280(6):595-608.
5. Lindblad-Toh K, Garber M, Zuk O, et al. A high-resolution map of human evolutionary
constraint using 29 mammals. Nature. 2011;478(7370):476-82.
6. DePristo MA, Banks E, Poplin R, et al. A framework for variation discovery and
genotyping using next-generation DNA sequencing data. Nature genetics. 2011;43(5):491-8.
7. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler
transform. Bioinformatics. 2009;25(14):1754-60.
8. Danecek P, Auton A, Abecasis G, et al. The variant call format and VCFtools.
Bioinformatics. 2011;27(15):2156-8.
9. Carson AR, Smith EN, Matsui H, et al. Effective filtering strategies to improve data
quality from population-based whole exome sequencing studies. BMC Bioinformatics. 2014;15:125.
10. Wang C, Zhan X, Bragg-Gresham J, et al. Ancestry estimation and control of population
stratification for sequence-based association studies. Nature genetics. 2014;46(4):409-15.
11. Wang C, Zhan X, Liang L, et al. Improved ancestry estimation for both genotyping and
sequencing data using projection procrustes analysis and genotype imputation. Am J Hum Genet.
2015;96(6):926-37.
12. Manichaikul A, Mychaleckyj JC, Rich SS, et al. Robust relationship inference in genome-
wide association studies. Bioinformatics. 2010;26(22):2867-73.
13. Do R, Stitziel NO, Won HH, et al. Exome sequencing identifies rare LDLR and APOA5
alleles conferring risk for myocardial infarction. Nature. 2015;518(7537):102-6.
14. Langefeld CD, Ainsworth HC, Cunninghame Graham DS, et al. Transancestral mapping
and genetic load in systemic lupus erythematosus. Nature communications. 2017;8:16021.
15. Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association
and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559-75.
16. Cingolani P, Platts A, Wang le L, et al. A program for annotating and predicting the
effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster
strain w1118; iso-2; iso-3. Fly. 2012;6(2):80-92.
17. Horton R, Wilming L, Rand V, et al. Gene map of the extended human MHC. Nature
reviews Genetics. 2004;5(12):889-99.
18. Cooper GM, Stone EA, Asimenos G, et al. Distribution and intensity of constraint in
mammalian genomic sequence. Genome Res. 2005;15(7):901-13.
19. Price AL, Patterson NJ, Plenge RM, et al. Principal components analysis corrects for
stratification in genome-wide association studies. Nature genetics. 2006;38(8):904-9.
20. Price AL, Weale ME, Patterson N, et al. Long-range LD can confound genome scans in
admixed populations. Am J Hum Genet. 2008;83(1):132-5; author reply 5-9.
21. RCoreTeam. R: A language and environment for statistical computing. R Foundation
for Statistical Computing, Vienna, Austria. 2013.
22. Turner SD. qqman: an R package for visualizing GWAS results using Q-Q and
manhattan plots. J Open Source Software. 2018;3(25):731.

23. Ameur A, Dahlberg J, Olason P, et al. SweGen: a whole-genome data resource of

genetic variability in a cross-section of the Swedish population. Eur J Hum Genet. 2017;25(11):1253-
60.
24. Karczewski KJ, Francioli LC, Tiao G, et al. Variation across 141,456 human exomes and
genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes.
bioRxiv. 2019:531210.
25. O'Leary NA, Wright MW, Brister JR, et al. Reference sequence (RefSeq) database at
NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res.
2016;44(D1):D733-45.
26. Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids
Res. 2000;28(1):27-30.
27. Rönnblom L, Leonard D. Interferon pathway in SLE: one key to unlocking the mystery
of the disease. Lupus Sci Med. 2019;6(1):e000270.
28. Rodero MP, Crow YJ. Type I interferon-mediated monogenic autoinflammation: The
type I interferonopathies, a conceptual overview. The Journal of experimental medicine.
2016;213(12):2527-38.
29. Davidson S, Steiner A, Harapas CR, et al. An Update on Autoinflammatory Diseases:
Interferonopathies. Current rheumatology reports. 2018;20(7):38.
30. Chen L, Morris DL, Vyse TJ. Genetic advances in systemic lupus erythematosus: an
update. Curr Opin Rheumatol. 2017;29(5):423-33.
31. Tsokos GC, Lo MS, Costa Reis P, et al. New insights into the immunopathogenesis of
systemic lupus erythematosus. Nat Rev Rheumatol. 2016;12(12):716-30.
32. Lee S, Emond MJ, Bamshad MJ, et al. Optimal unified approach for rare-variant
association testing with application to small-sample case-control whole-exome sequencing studies.
Am J Hum Genet. 2012;91(2):224-37.
33. Mossotto E, Ashton JJ, O'Gorman L, et al. GenePy - a score for estimating gene
pathogenicity in individuals using next-generation sequencing data. BMC Bioinformatics.
2019;20(1):254.
34. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants
from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164.
35. Ioannidis NM, Rothstein JH, Pejaver V, et al. REVEL: An Ensemble Method for
Predicting the Pathogenicity of Rare Missense Variants. Am J Hum Genet. 2016;99(4):877-85.
36. Rentzsch P, Witten D, Cooper GM, et al. CADD: predicting the deleteriousness of
variants throughout the human genome. Nucleic Acids Res. 2019;47(D1):D886-D94.
37. Charrad M. GN, Boiteau V., Niknafs A. NbClust: An R Package for Determining the
Relevant Number of Clusters in a Data Set. J of Statistical Software. 2014;61(6):1-36.
38. Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in
multidimensional genomic data. Bioinformatics. 2016;32(18):2847-9.
39. Thorlacius GE, Hultin-Rosenberg L, Sandling JK, et al. Genetic and clinical basis for two
distinct subtypes of primary Sjogren's syndrome. Rheumatology (Oxford). 2020.
40. McCarthy S, Das S, Kretzschmar W, et al. A reference panel of 64,976 haplotypes for
genotype imputation. Nature genetics. 2016;48(10):1279-83.

Supplementary Table S1a. Patient characteristics Scandinavian SLE cohorts.

Sweden Norway Denmark P† Pbonferroni‡
Number of patients 958 289 547
Female 826 (86.2%) 258 (89.3%) 484 (89.6%) 0.036 0.54
Age at diagnosis 36 (3-85) 32 (9-73) 33 (3-80) 9.5E-07 1.4E-05
Age at follow-up 52 (18-94) 52 (23-90) 47 (18-80) 8.4E-06 0.00013
Deceased (all causes)* 74 (7.7%) - - - -
Deceased age 68 (27-91) - - - -
≥4 ACR criteria (Tan et al., 1982; Hochberg et al., 1997) 958 (100%) 289 (100%) 547 (100%) 1 1
Number of ACR criteria fulfilled 5.7 (4-10) 5.9 (4-9) 5.9 (4-11) 0.00094 0.014
ACR criteria:
1) Malar rash 543 (56.7%) 171 (59.4%) 323 (59.0%) 0.29 1
2) Discoid rash 235 (24.5%) 36 (12.5%) 51 (9.3%) 3.9E-15 5.9E-14
3) Photosensitivity 648 (67.6%) 208 (73.5%) 307 (56.1%) 0.015 0.22
4) Oral Ulcers 241 (25.2%) 95 (33.8%) 160 (29.3%) 0.0081 0.12
5) Arthritis 754 (78.7%) 224 (77.8%) 459 (83.9%) 0.11 1
6) Serositis 409 (42.7%) 113 (39.1%) 224 (41.0%) 0.31 1
7) Renal disorder 338 (35.3%) 115 (40.2%) 239 (43.7%) 0.0019 0.028
8) Neurologic disorder 99 (10.3%) 23 (8.0%) 65 (11.9%) 0.94 1
9) Hematologic disorder 615 (64.2%) 206 (75.2%) 398 (72.8%) 2.1E-05 3.2E-04
10) Immunologic disorder 653 (68.2%) 227 (80.8%) 491 (89.9%) < 2.2E-16 3.3E-15
11) Positive ANA 942 (98.3%) 288 (100%) 537 (98.2%) 0.44 1
Autoantibodies:
Anti-DNA 449 (61.8%) - - - -
Anti-Sm 99 (13.6%) - - - -
Anti-RNP 188 (26.1%) - - - -
Anti-SSA 351 (37.3%) - - - -
Anti-SSB 206 (21.8%) - - - -
Anti-cardiolipin IgG 243 (25.9%) - - - -
Anti-beta2-glycoprotein I IgG 179 (19.8%) - - - -
Rheumatoid factor (RF) 130 (23.9%) - - - -
Lupus anticoagulant (LAC) 137 (22.6%) - - - -
SLICC Damage Index (Gladman et al., 1996) 2.2 (0-14) - - - -
Data are number (%) or mean (range) excluding patients with missing data.
ACR: the American College of Rheumatology
SLICC: The Systemic Lupus Erythematosus International Collaborating Clinics
*An extended follow-up point was also added for death at which a total of 157 (16.4%) patients were recorded as
deceased at an mean age of 68 (27-96) years.
†Categorical variables were compared using a Fisher's exact test and continuous variables by Student’s unpaired t-
test. The Swedish patients were compared to the combined Norwegian and Danish cohort.
‡Bonferroni corrected P-value, corrected for 15 tests.
Supplementary Table S1b. Clinical information on lupus nephritis Swedish SLE cohort.
Sweden (number of
patients)
Renal disorder 338
Renal biopsy data 257
Biopsy confirmed nephritis* 245
Class I-II 33
Class III-IV 153
Class V 41
Other 18
Dialysis or transplantation (ESRD) 35
*Biopsies were classified according to the WHO or the ISN/RPS 2003 classification systems.
ESRD: End-Stage Renal Disease

Supplementary Table S2. 35 analysed KEGG pathways and their genes. Each pathway included at least five genes and half or more of genes needed to be included in the targeted sequencing effort. Only sequenced
genes are listed.
Pathway (KEGG ID) Genes (RefSeq)

Adherens junction (hsa04520) ACTN1, ACTN4, AFDN, CDC42, CDH1, CREBBP, CTNNA1, CTNNB1, CTNND1, EGFR, EP300, ERBB2, FER, FYN, INSR, IQGAP1, LMO7, MAP3K7, MAPK1, MAPK3,
MET, NECTIN2, PTPN1, PTPN6, PTPRM, RAC1, RAC2, RAC3, RHOA, SMAD3, SMAD4, SNAI1, SORBS1, SRC, TCF7, TGFBR1, TGFBR2, VCL, WAS, WASL, YES1
Antigen processing and presentation (hsa04612) B2M, CALR, CANX, CD4, CD74, CD8A, CD8B, CIITA, CREB1, HLA-A, HLA-B, HLA-C, HLA-DOA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2, HLA-
DQB1, HLA-DRA, HLA-DRB1, HLA-DRB5, HLA-E, HSPA6, HSPA8, IFNG, KIR2DL1, KIR2DL3, KLRC1, KLRC2, KLRC3, KLRD1, PDIA3, RFX5, RFXANK, RFXAP, TAP1,
TAP2, TAPBP, TNF
Apoptosis - multiple species (hsa04215) APAF1, BAK1, BAX, BCL2, BCL2L1, BCL2L11, BID, BIRC2, BIRC3, BIRC6, CASP3, CASP8, CASP9, CYCS, FADD, MAPK10, MAPK8, MAPK9, NGFR, TNFRSF1A
Apoptosis (hsa04210) AIFM1, AKT1, APAF1, ATM, BAD, BAK1, BAX, BCL2, BCL2A1, BCL2L1, BCL2L11, BID, BIRC2, BIRC3, CAPN1, CAPN2, CASP10, CASP2, CASP3, CASP8, CASP9,
CFLAR, CHUK, CSF2RB, CTSH, CTSK, CYCS, DAXX, DDIT3, DFFA, EIF2S1, ENDOG, FADD, FAS, FASLG, FOS, GADD45B, GADD45G, GZMB, HRAS, IKBKB, IKBKG,
IL3, ITPR1, JUN, KRAS, MAP2K1, MAP2K2, MAP3K14, MAP3K5, MAPK1, MAPK10, MAPK3, MAPK8, MAPK9, NFKB1, NFKBIA, NGF, NRAS, NTRK1, PARP1,
PIK3CA, PIK3CB, PIK3CD, PRF1, RAF1, RELA, RIPK1, TNF, TNFRSF1A, TNFSF10, TP53, TRADD, TRAF1, TRAF2
B cell receptor signaling pathway (hsa04662) AKT1, BCL10, BLNK, BTK, CARD11, CD19, CD22, CD79A, CD79B, CD81, CHUK, CR2, DAPP1, FCGR2B, FOS, GRB2, GSK3B, HRAS, IFITM1, IKBKB, IKBKG, INPP5D,
JUN, KRAS, LILRB1, LILRB4, LYN, MALT1, MAP2K1, MAP2K2, MAPK1, MAPK3, NFATC1, NFATC2, NFATC3, NFKB1, NFKBIA, NFKBIB, NRAS, PIK3CA, PIK3CB,
PIK3CD, PLCG2, PPP3CA, PPP3CB, PPP3CC, PPP3R1, PPP3R2, PRKCB, PTPN6, RAC1, RAC2, RAC3, RAF1, RASGRP3, RELA, SOS1, SYK, VAV1, VAV2
Chemokine signaling pathway (hsa04062) ADCY2, ADCY3, AKT1, BAD, BRAF, CCL1, CCL11, CCL13, CCL19, CCL2, CCL21, CCL24, CCL25, CCL26, CCL3, CCL3L3, CCL4, CCL5, CCL7, CCR1, CCR10, CCR2,
CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CDC42, CHUK, CRK, CRKL, CX3CL1, CX3CR1, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL16, CXCL2,
CXCL3, CXCL5, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, ELMO1, FGR, FOXO3, GRB2, GSK3B, HCK, HRAS, IKBKB, IKBKG, ITK, JAK2, JAK3,
KRAS, LYN, MAP2K1, MAPK1, MAPK3, NCF1, NFKB1, NFKBIA, NFKBIB, NRAS, PAK1, PF4, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PLCB2, PPBP, PREX1, PRKCB,
PRKCD, PRKCZ, PTK2, PTK2B, PXN, RAC1, RAC2, RAC3, RAF1, RELA, RHOA, ROCK1, ROCK2, SHC1, SOS1, SRC, STAT1, STAT2, STAT3, STAT5B, VAV1, VAV2,
WAS, WASL, XCR1
Complement and coagulation cascades (hsa04610) A2M, C1QA, C1QB, C1QC, C1R, C1S, C2, C3, C3AR1, C4A, C4B, C4BPA, C5, C5AR1, C6, C7, C9, CD46, CD55, CD59, CFB, CFD, CFH, CFI, CR1, CR2, F11, F12, F2,
F2R, F8, FGA, FGB, FGG, ITGAM, ITGAX, ITGB2, KLKB1, MASP1, MASP2, MBL2, PLAT, PLAU, PLG, PROS1, SERPINA1, SERPIND1, SERPINE1, SERPING1, VWF
C-type lectin receptor signaling pathway (hsa04625) AKT1, ARHGEF12, BCL10, BCL3, CARD9, CASP1, CASP8, CBLB, CD209, CHUK, CLEC7A, CYLD, FCER1G, HRAS, IKBKB, IKBKE, IKBKG, IL10, IL12A, IL12B, IL1B, IL2,
IL23A, IL6, IRF1, IRF9, ITPR1, JUN, KRAS, LSP1, MALT1, MAP3K14, MAPK1, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, MAPK8, MAPK9,
MAPKAPK2, MDM2, NFATC1, NFATC2, NFATC3, NFATC4, NFKB1, NFKB2, NFKBIA, NLRP3, NRAS, PAK1, PIK3CA, PIK3CB, PIK3CD, PLCG2, PPP3CA, PPP3CB,
PPP3CC, PPP3R1, PPP3R2, PRKCD, PTGS2, PTPN11, PYCARD, RAF1, RELA, RELB, RHOA, SRC, STAT1, STAT2, SYK, TNF
Cytokine-cytokine receptor interaction (hsa04060) ACKR3, ACVR1, ACVR1B, ACVR2A, ACVR2B, AMH, AMHR2, BMPR1A, BMPR1B, BMPR2, CCL1, CCL11, CCL13, CCL19, CCL2, CCL21, CCL24, CCL25, CCL26, CCL3,
CCL3L3, CCL4, CCL5, CCL7, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD27, CD4, CD40, CD40LG, CD70, CLCF1, CNTF, CNTFR, CSF1,
CSF1R, CSF2, CSF2RB, CSF3, CSF3R, CTF1, CX3CL1, CX3CR1, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL16, CXCL2, CXCL3, CXCL5, CXCL8, CXCL9,
CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, EDA, EDA2R, EDAR, EPO, EPOR, FAS, FASLG, GH1, GHR, IFNA1, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17,
IFNA2, IFNA21, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNAR1, IFNAR2, IFNB1, IFNE, IFNG, IFNGR1, IFNGR2, IFNK, IFNL1, IFNLR1, IFNW1, IL10, IL10RA, IL10RB,
IL11, IL11RA, IL12A, IL12B, IL12RB1, IL12RB2, IL13, IL13RA1, IL13RA2, IL15, IL15RA, IL17A, IL17B, IL17F, IL17RA, IL17RB, IL17RC, IL18, IL18R1, IL18RAP, IL19,
IL1A, IL1B, IL1R1, IL1R2, IL1RAP, IL1RL1, IL1RL2, IL1RN, IL2, IL20, IL20RA, IL20RB, IL21, IL21R, IL22, IL22RA1, IL23A, IL23R, IL24, IL25, IL26, IL27, IL27RA,
IL2RA, IL2RB, IL2RG, IL3, IL32, IL4, IL4R, IL5, IL5RA, IL6, IL6R, IL6ST, IL7, IL7R, IL9, LEP, LEPR, LIF, LIFR, LTA, LTB, LTBR, MPL, NGF, NGFR, OSM, OSMR, PF4,
PPBP, PRL, PRLR, RELT, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, TNF, TNFRSF11A, TNFRSF11B, TNFRSF12A, TNFRSF13B, TNFRSF13C, TNFRSF14, TNFRSF17,
TNFRSF18, TNFRSF19, TNFRSF1A, TNFRSF1B, TNFRSF21, TNFRSF25, TNFRSF4, TNFRSF6B, TNFRSF8, TNFRSF9, TNFSF10, TNFSF11, TNFSF12, TNFSF13,
TNFSF13B, TNFSF14, TNFSF15, TNFSF18, TNFSF4, TNFSF8, TNFSF9, TSLP, XCR1

Cytosolic DNA-sensing pathway (hsa04623) ADAR, AIM2, CASP1, CCL4, CCL5, CHUK, CXCL10, DDX58, IFNA1, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA2, IFNA21, IFNA4, IFNA5, IFNA6, IFNA7,
IFNA8, IFNB1, IKBKB, IKBKE, IKBKG, IL18, IL1B, IL6, IRF3, IRF7, MAVS, NFKB1, NFKBIA, NFKBIB, PYCARD, RELA, RIPK1, TBK1, TREX1, ZBP1
ErbB signaling pathway (hsa04012) ABL1, AKT1, BAD, BRAF, CBL, CBLB, CDKN1B, CRK, CRKL, EGF, EGFR, EIF4EBP1, ELK1, ERBB2, ERBB3, GAB1, GRB2, GSK3B, HBEGF, HRAS, JUN, KRAS,
MAP2K1, MAP2K2, MAP2K4, MAP2K7, MAPK1, MAPK10, MAPK3, MAPK8, MAPK9, MTOR, MYC, NCK1, NRAS, NRG1, PAK1, PAK2, PIK3CA, PIK3CB, PIK3CD,
PLCG1, PLCG2, PRKCA, PRKCB, PTK2, RAF1, RPS6KB1, SHC1, SOS1, SRC, STAT5A, STAT5B, TGFA
Fc epsilon RI signaling pathway (hsa04664) AKT1, BTK, CSF2, FCER1A, FCER1G, FYN, GAB2, GRB2, HRAS, IL13, IL3, IL4, IL5, INPP5D, KRAS, LAT, LCP2, LYN, MAP2K1, MAP2K2, MAP2K3, MAP2K4,
MAP2K6, MAP2K7, MAPK1, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, MAPK8, MAPK9, MS4A2, NRAS, PIK3CA, PIK3CB, PIK3CD, PLCG1,
PLCG2, PRKCA, RAC1, RAC2, RAC3, RAF1, SOS1, SYK, TNF, VAV1, VAV2
Fc gamma R-mediated phagocytosis (hsa04666) AKT1, AMPH, ARF6, ASAP1, ASAP2, CDC42, CFL1, CRK, CRKL, DNM2, FCGR1A, FCGR2A, FCGR2B, FCGR3B, GAB2, GSN, HCK, INPP5D, LAT, LYN, MAP2K1,
MAPK1, MAPK3, NCF1, PAK1, PIK3CA, PIK3CB, PIK3CD, PIP5K1A, PIP5K1C, PLA2G6, PLCG1, PLCG2, PRKCA, PRKCB, PRKCD, PRKCE, PTPRC, RAC1, RAC2, RAF1,
RPS6KB1, SYK, VASP, VAV1, VAV2, WAS, WASL
FoxO signaling pathway (hsa04068) AKT1, ATM, BCL2L11, BCL6, BRAF, CAT, CCND1, CDK2, CDKN1B, CDKN2B, CHUK, CREBBP, EGF, EGFR, EP300, FASLG, FOXG1, FOXO1, FOXO3, GADD45B,
GADD45G, GRB2, HOMER2, HOMER3, HRAS, IGF1, IKBKB, IL10, IL6, IL7R, INS, INSR, IRS1, KRAS, MAP2K1, MAP2K2, MAPK1, MAPK10, MAPK11, MAPK12,
MAPK13, MAPK14, MAPK3, MAPK8, MAPK9, MDM2, NRAS, PIK3CA, PIK3CB, PIK3CD, PTEN, RAF1, RAG1, RAG2, SMAD3, SMAD4, SOD2, SOS1, STAT3,
TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, TNFSF10
Hematopoietic cell lineage (hsa04640) CD14, CD19, CD1A, CD1B, CD1C, CD1D, CD22, CD36, CD38, CD3D, CD3E, CD4, CD44, CD5, CD55, CD59, CD8A, CD8B, CR1, CR2, CSF1, CSF1R, CSF2, CSF3,
CSF3R, DNTT, EPO, EPOR, FCER2, FCGR1A, FLT3, FLT3LG, GYPA, HLA-DOA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRA,
HLA-DRB1, HLA-DRB5, IL11, IL11RA, IL1A, IL1B, IL1R1, IL1R2, IL2RA, IL3, IL4, IL4R, IL5, IL5RA, IL6, IL6R, IL7, IL7R, ITGA2, ITGA3, ITGA4, ITGA5, ITGAM, KIT,
KITLG, TFRC, TNF
HIF-1 signaling pathway (hsa04066) AKT1, ANGPT1, ANGPT2, ARNT, BCL2, CDKN1B, CREBBP, CYBB, EGF, EGFR, EIF4E, EIF4EBP1, ENO1, ENO2, ENO3, EP300, EPO, ERBB2, FLT1, HIF1A, HMOX1,
IFNG, IFNGR1, IFNGR2, IGF1, IL6, IL6R, INS, INSR, LTBR, MAP2K1, MAP2K2, MAPK1, MAPK3, MTOR, NFKB1, NOS2, PDHB, PDK1, PFKL, PFKM, PGK1, PIK3CA,
PIK3CB, PIK3CD, PLCG1, PLCG2, PRKCA, PRKCB, RELA, RPS6KB1, SERPINE1, SLC2A1, STAT3, TEK, TF, TFRC, TIMP1, TLR4, VEGFA
IL-17 signaling pathway (hsa04657) CASP3, CASP8, CCL11, CCL2, CCL7, CEBPB, CHUK, CSF2, CSF3, CXCL1, CXCL10, CXCL2, CXCL3, CXCL5, CXCL8, DEFB4A, FADD, FOS, GSK3B, IFNG, IKBKB, IKBKE,
IKBKG, IL13, IL17A, IL17B, IL17F, IL17RA, IL17RB, IL17RC, IL1B, IL25, IL4, IL5, IL6, JUN, JUND, MAP3K7, MAPK1, MAPK10, MAPK11, MAPK12, MAPK13,
MAPK14, MAPK3, MAPK7, MAPK8, MAPK9, MMP1, MMP13, MMP3, MMP9, MUC5B, NFKB1, NFKBIA, PTGS2, RELA, TAB2, TAB3, TBK1, TNF, TNFAIP3,
TRADD, TRAF2, TRAF3, TRAF3IP2, TRAF5, TRAF6
Intestinal immune network for IgA production (hsa04672) AICDA, CCL25, CCR10, CCR9, CD28, CD40, CD40LG, CD80, CD86, CXCL12, CXCR4, HLA-DOA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2, HLA-
DQB1, HLA-DRA, HLA-DRB1, HLA-DRB5, ICOS, ICOSLG, IL10, IL15, IL15RA, IL2, IL4, IL5, IL6, ITGA4, LTBR, MAP3K14, TGFB1, TNFRSF13B, TNFRSF13C,
TNFRSF17, TNFSF13, TNFSF13B
JAK-STAT signaling pathway (hsa04630) AKT1, BCL2, BCL2L1, CCND1, CISH, CNTF, CNTFR, CREBBP, CSF2, CSF2RB, CSF3, CSF3R, CTF1, EGF, EGFR, EP300, EPO, EPOR, GH1, GHR, GRB2, HRAS, IFNA1,
IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA2, IFNA21, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNAR1, IFNAR2, IFNB1, IFNE, IFNG, IFNGR1, IFNGR2, IFNK,
IFNL1, IFNLR1, IFNW1, IL10, IL10RA, IL10RB, IL11, IL11RA, IL12A, IL12B, IL12RB1, IL12RB2, IL13, IL13RA1, IL13RA2, IL15, IL15RA, IL19, IL2, IL20, IL20RA,
IL20RB, IL21, IL21R, IL22, IL22RA1, IL22RA2, IL23A, IL23R, IL24, IL27RA, IL2RA, IL2RB, IL2RG, IL3, IL4, IL4R, IL5, IL5RA, IL6, IL6R, IL6ST, IL7, IL7R, IL9, IRF9,
JAK1, JAK2, JAK3, LEP, LEPR, LIF, LIFR, MPL, MTOR, MYC, OSM, OSMR, PDGFRA, PDGFRB, PIAS1, PIK3CA, PIK3CB, PIK3CD, PIM1, PRL, PRLR, PTPN11, PTPN2,
PTPN6, RAF1, SOCS1, SOCS2, SOCS3, SOCS6, SOS1, STAM, STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6, TSLP, TYK2
Leukocyte transendothelial migration (hsa04670) ACTN1, ACTN4, AFDN, CDC42, CDH5, CLDN1, CLDN19, CLDN5, CTNNA1, CTNNB1, CTNND1, CXCL12, CXCR4, CYBA, CYBB, EZR, F11R, ICAM1, ITGA4, ITGAL,
ITGAM, ITGB1, ITGB2, ITK, JAM2, JAM3, MAPK11, MAPK12, MAPK13, MAPK14, MMP2, MMP9, NCF1, NCF2, NCF4, PECAM1, PIK3CA, PIK3CB, PIK3CD,
PLCG1, PLCG2, PRKCA, PRKCB, PTK2, PTK2B, PTPN11, PXN, RAC1, RAC2, RASSF5, RHOA, RHOH, ROCK1, ROCK2, SIPA1, THY1, VASP, VAV1, VAV2, VCAM1,
VCL

MAPK signaling pathway (hsa04010) AKT1, ANGPT1, ANGPT2, ATF2, BRAF, CACNA1H, CACNA1S, CACNA2D2, CASP3, CD14, CDC42, CHUK, CRK, CRKL, CSF1, CSF1R, DAXX, DDIT3, DUSP1, ECSIT,
EGF, EGFR, ELK1, ERBB2, ERBB3, FAS, FASLG, FGF10, FGF7, FLNB, FLT1, FLT3, FLT3LG, FLT4, FOS, GADD45B, GADD45G, GNA12, GRB2, HGF, HRAS, HSPA6,
HSPA8, IGF1, IKBKB, IKBKG, IL1A, IL1B, IL1R1, IL1RAP, INS, INSR, IRAK1, IRAK4, JUNE, JUND, KDR, KIT, KITLG, KRAS, LAMTOR3, MAP2K1, MAP2K2, MAP2K3,
MAP2K4, MAP2K5, MAP2K6, MAP2K7, MAP3K1, MAP3K14, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K6, MAP3K7, MAP3K8, MAP4K1, MAP4K3,
MAPK1, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, MAPK7, MAPK8, MAPK9, MAPKAPK2, MAPKAPK5, MAX, MET, MYC, MYD88, NFATC1,
NFATC3, NFKB1, NFKB2, NGF, NGFR, NR4A1, NRAS, NTF3, NTRK1, PAK1, PAK2, PDGFRA, PDGFRB, PPP3CA, PPP3CB, PPP3CC, PPP3R1, PPP3R2, PRKCA,
PRKCB, PTPN7, RAC1, RAC2, RAC3, RAF1, RASA1, RASGRP1, RASGRP3, RELA, RELB, RPS6KA1, RPS6KA4, SOS1, SRF, TAB1, TAB2, TEK, TGFA, TGFB1, TGFB2,
TGFB3, TGFBR1, TGFBR2, TNF, TNFRSF1A, TP53, TRADD, TRAF2, TRAF6, VEGFA, VEGFB, VEGFC, VEGFD
Natural killer cell mediated cytotoxicity (hsa04650) BID, BRAF, CASP3, CD244, CD247, CD48, CSF2, FAS, FASLG, FCER1G, FCGR3B, FYN, GRB2, GZMB, HCST, HLA-A, HLA-B, HLA-C, HLA-E, HRAS, ICAM1, IFNA1,
IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA2, IFNA21, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNAR1, IFNAR2, IFNB1, IFNG, IFNGR1, IFNGR2, ITGAL, ITGB2,
KIR2DL1, KIR2DL3, KLRC1, KLRC2, KLRC3, KLRD1, KLRK1, KRAS, LAT, LCK, LCP2, MAP2K1, MAP2K2, MAPK1, MAPK3, MICA, MICB, NCR1, NCR2, NCR3,
NFATC1, NFATC2, NRAS, PAK1, PIK3CA, PIK3CB, PIK3CD, PLCG1, PLCG2, PPP3CA, PPP3CB, PPP3CC, PPP3R1, PPP3R2, PRF1, PRKCA, PRKCB, PTK2B, PTPN11,
PTPN6, RAC1, RAC2, RAC3, RAET1L, RAF1, SH2D1A, SH2D1B, SH3BP2, SHC1, SOS1, SYK, TNF, TNFSF10, TYROBP, ULBP3, VAV1, VAV2, ZAP70
Neurotrophin signaling pathway (hsa04722) ABL1, AKT1, BAD, BAX, BCL2, BRAF, CDC42, CRK, CRKL, FASLG, FOXO3, GAB1, GRB2, GSK3B, HRAS, IKBKB, IRAK1, IRAK2, IRAK3, IRAK4, IRS1, JUN, KRAS,
MAP2K1, MAP2K2, MAP2K5, MAP2K7, MAP3K1, MAP3K3, MAP3K5, MAPK1, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, MAPK7, MAPK8,
MAPK9, MAPKAPK2, NFKB1, NFKBIA, NFKBIB, NGF, NGFR, NRAS, NTF3, NTRK1, PIK3CA, PIK3CB, PIK3CD, PLCG1, PLCG2, PRKCD, PTPN11, RAC1, RAF1,
RAPGEF1, RELA, RHOA, RIPK2, RPS6KA1, SH2B1, SH2B3, SHC1, SOS1, TP53, TRAF6
NF-kappa B signaling pathway (hsa04064) ATM, BCL10, BCL2, BCL2A1, BCL2L1, BIRC2, BIRC3, BLNK, BTK, CARD10, CARD11, CCL13, CCL19, CCL21, CCL4, CD14, CD40, CD40LG, CFLAR, CHUK, CXCL1,
CXCL12, CXCL2, CXCL3, CXCL8, CYLD, DDX58, EDA, EDA2R, EDAR, GADD45B, ICAM1, IKBKB, IKBKG, IL1B, IL1R1, IRAK1, IRAK4, LAT, LBP, LCK, LTA, LTB, LTBR,
LY96, LYN, MALT1, MAP3K14, MAP3K7, MYD88, NFKB1, NFKB2, NFKBIA, PARP1, PLAU, PLCG1, PLCG2, PRKCB, PRKCQ, PTGS2, RELA, RELB, RIPK1, SYK, TAB1,
TAB2, TAB3, TICAM1, TICAM2, TIRAP, TLR4, TNF, TNFAIP3, TNFRSF11A, TNFRSF13C, TNFRSF1A, TNFSF11, TNFSF13B, TNFSF14, TRADD, TRAF1, TRAF2,
TRAF3, TRAF5, TRAF6, TRIM25, VCAM1, ZAP70
NOD-like receptor signaling pathway (hsa04621) AIM2, ANTXR2, ATG16L1, BCL2, BCL2L1, BIRC2, BIRC3, CARD9, CASP1, CASP5, CASP8, CASR, CCL2, CCL5, CHUK, CXCL1, CXCL2, CXCL3, CXCL8, CYBA, CYBB,
DEFA1, DEFB4A, DNM1L, FADD, IFI16, IFNA1, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA2, IFNA21, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNAR1,
IFNAR2, IFNB1, IKBKB, IKBKE, IKBKG, IL18, IL1B, IL6, IRAK4, IRF3, IRF7, IRF9, ITPR1, JAK1, JUN, MAP3K7, MAPK1, MAPK10, MAPK11, MAPK12, MAPK13,
MAPK14, MAPK3, MAPK8, MAPK9, MAVS, MEFV, MYD88, NAIP, NFKB1, NFKBIA, NFKBIB, NLRC4, NLRP1, NLRP12, NLRP3, NLRP7, NLRX1, NOD1, NOD2,
OAS1, OAS2, PLCB2, PRKCD, PSTPIP1, PYCARD, RELA, RHOA, RIPK1, RIPK2, RNASEL, STAT1, STAT2, TAB1, TAB2, TAB3, TANK, TBK1, TICAM1, TLR4, TNF,
TNFAIP3, TRAF2, TRAF3, TRAF5, TRAF6, TRPM7, TXN, TYK2
Osteoclast differentiation (hsa04380) ACP5, AKT1, BLNK, BTK, CHUK, CREB1, CSF1, CSF1R, CTSK, CYBA, CYLD, FCGR1A, FCGR2A, FCGR2B, FCGR3B, FOS, FOSL2, FYN, GAB2, GRB2, IFNAR1, IFNAR2,
IFNB1, IFNG, IFNGR1, IFNGR2, IKBKB, IKBKG, IL1A, IL1B, IL1R1, IRF9, JAK1, JUN, JUNB, JUND, LCK, LCP2, LILRB1, LILRB4, MAP2K1, MAP2K6, MAP2K7,
MAP3K14, MAP3K7, MAPK1, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, MAPK8, MAPK9, MITF, NCF1, NCF2, NCF4, NFATC1, NFATC2, NFKB1,
NFKB2, NFKBIA, NOX1, OSCAR, PIK3CA, PIK3CB, PIK3CD, PLCG2, PPARG, PPP3CA, PPP3CB, PPP3CC, PPP3R1, PPP3R2, RAC1, RELA, RELB, SIRPA, SOCS1,
SOCS3, SPI1, STAT1, STAT2, SYK, TAB1, TAB2, TGFB1, TGFB2, TGFBR1, TGFBR2, TNF, TNFRSF11A, TNFRSF11B, TNFRSF1A, TNFSF11, TRAF2, TRAF6, TREM2,
TYK2, TYROBP
Prolactin signaling pathway (hsa04917) AKT1, CCND1, CGA, CISH, CSN2, CYP17A1, ESR1, ESR2, FOS, FOXO3, GRB2, GSK3B, HRAS, INS, IRF1, JAK2, KRAS, MAP2K1, MAP2K2, MAPK1, MAPK10,
MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, MAPK8, MAPK9, NFKB1, NRAS, PIK3CA, PIK3CB, PIK3CD, PRL, PRLR, RAF1, RELA, SHC1, SOCS1, SOCS2,
SOCS3, SOCS6, SOS1, SRC, STAT1, STAT3, STAT5A, STAT5B, TH, TNFRSF11A, TNFSF11
RIG-I-like receptor signaling pathway (hsa04622) AZI2, CASP10, CASP8, CHUK, CXCL10, CXCL8, CYLD, DDX58, DHX58, FADD, IFIH1, IFNA1, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA2, IFNA21, IFNA4,
IFNA5, IFNA6, IFNA7, IFNA8, IFNB1, IFNE, IFNK, IFNW1, IKBKB, IKBKE, IKBKG, IL12A, IL12B, IRF3, IRF7, ISG15, MAP3K1, MAP3K7, MAPK10, MAPK11,
MAPK12, MAPK13, MAPK14, MAPK8, MAPK9, MAVS, NFKB1, NFKBIA, NFKBIB, NLRX1, PIN1, RELA, RIPK1, SIKE1, TANK, TBK1, TBKBP1, TNF, TRADD, TRAF2,
TRAF3, TRAF6, TRIM25

T cell receptor signaling pathway (hsa04660) AKT1, BCL10, CARD11, CBLB, CD247, CD28, CD3D, CD3E, CD4, CD40LG, CD8A, CD8B, CDC42, CDK4, CHUK, CSF2, CTLA4, FOS, FYN, GRAP2, GRB2, GSK3B,
HRAS, ICOS, IFNG, IKBKB, IKBKG, IL10, IL2, IL4, IL5, ITK, JUN, KRAS, LAT, LCK, LCP2, MALT1, MAP2K1, MAP2K2, MAP2K7, MAP3K14, MAP3K7, MAP3K8,
MAPK1, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, MAPK8, MAPK9, NCK1, NFATC1, NFATC2, NFATC3, NFKB1, NFKBIA, NFKBIB, NRAS, PAK1,
PAK2, PIK3CA, PIK3CB, PIK3CD, PLCG1, PPP3CA, PPP3CB, PPP3CC, PPP3R1, PPP3R2, PRKCQ, PTPN6, PTPRC, RAF1, RASGRP1, RELA, RHOA, SOS1, TNF, VAV1,
VAV2, ZAP70
Th1 and Th2 cell differentiation (hsa04658) CD247, CD3D, CD3E, CD4, CHUK, FOS, GATA3, HLA-DOA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRA, HLA-DRB1, HLA-
DRB5, IFNG, IFNGR1, IFNGR2, IKBKB, IKBKG, IL12A, IL12B, IL12RB1, IL12RB2, IL13, IL2, IL2RA, IL2RB, IL2RG, IL4, IL4R, IL5, JAK1, JAK2, JAK3, JUN, LAT, LCK,
MAF, MAML1, MAPK1, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, MAPK8, MAPK9, NFATC1, NFATC2, NFATC3, NFKB1, NFKBIA, NFKBIB,
NOTCH1, NOTCH2, NOTCH3, PLCG1, PPP3CA, PPP3CB, PPP3CC, PPP3R1, PPP3R2, PRKCQ, RBPJ, RELA, RUNX3, STAT1, STAT4, STAT5A, STAT5B, STAT6,
TBX21, TYK2, ZAP70
Th17 cell differentiation (hsa04659) AHR, CD247, CD3D, CD3E, CD4, CHUK, FOS, FOXP3, GATA3, HIF1A, HLA-DOA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRA,
HLA-DRB1, HLA-DRB5, IFNG, IFNGR1, IFNGR2, IKBKB, IKBKG, IL12RB1, IL17A, IL17F, IL1B, IL1R1, IL1RAP, IL2, IL21, IL21R, IL22, IL23A, IL23R, IL27RA, IL2RA,
IL2RB, IL2RG, IL4, IL4R, IL6, IL6R, IL6ST, IRF4, JAK1, JAK2, JAK3, JUN, LAT, LCK, MAPK1, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, MAPK8,
MAPK9, MTOR, NFATC1, NFATC2, NFATC3, NFKB1, NFKBIA, NFKBIB, PLCG1, PPP3CA, PPP3CB, PPP3CC, PPP3R1, PPP3R2, PRKCQ, RARA, RELA, RORA, RORC,
RUNX1, RXRA, SMAD2, SMAD4, STAT1, STAT3, STAT5A, STAT5B, STAT6, TBX21, TGFB1, TGFBR1, TGFBR2, TYK2, ZAP70
TNF signaling pathway (hsa04668) AKT1, ATF2, BAG4, BCL3, BIRC2, BIRC3, CASP10, CASP3, CASP8, CCL2, CCL5, CEBPB, CFLAR, CHUK, CREB1, CSF1, CSF2, CX3CL1, CXCL1, CXCL10, CXCL2, CXCL3,
CXCL5, DNM1L, FADD, FAS, FOS, ICAM1, IFNB1, IKBKB, IKBKG, IL15, IL18R1, IL1B, IL6, IRF1, JUN, JUNB, LIF, LTA, MAP2K1, MAP2K3, MAP2K4, MAP2K6,
MAP2K7, MAP3K14, MAP3K5, MAP3K7, MAP3K8, MAPK1, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, MAPK8, MAPK9, MMP14, MMP3,
MMP9, NFKB1, NFKBIA, NOD2, PIK3CA, PIK3CB, PIK3CD, PTGS2, RELA, RIPK1, RPS6KA4, SELE, SOCS3, TAB1, TAB2, TAB3, TNF, TNFAIP3, TNFRSF1A,
TNFRSF1B, TRADD, TRAF1, TRAF2, TRAF3, TRAF5, VCAM1, VEGFC, VEGFD
Toll-like receptor signaling pathway (hsa04620) AKT1, CASP8, CCL3, CCL3L3, CCL4, CCL5, CD14, CD40, CD80, CD86, CHUK, CTSK, CXCL10, CXCL11, CXCL8, CXCL9, FADD, FOS, IFNA1, IFNA10, IFNA13, IFNA14,
IFNA16, IFNA17, IFNA2, IFNA21, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNAR1, IFNAR2, IFNB1, IKBKB, IKBKE, IKBKG, IL12A, IL12B, IL1B, IL6, IRAK1, IRAK4,
IRF3, IRF5, IRF7, JUN, LBP, LY96, MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K6, MAP2K7, MAP3K7, MAP3K8, MAPK1, MAPK10, MAPK11, MAPK12,
MAPK13, MAPK14, MAPK3, MAPK8, MAPK9, MYD88, NFKB1, NFKBIA, PIK3CA, PIK3CB, PIK3CD, RAC1, RELA, RIPK1, SPP1, STAT1, TAB1, TAB2, TBK1,
TICAM1, TICAM2, TIRAP, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNF, TOLLIP, TRAF3, TRAF6
VEGF signaling pathway (hsa04370) AKT1, BAD, CASP9, CDC42, HRAS, KDR, KRAS, MAP2K1, MAP2K2, MAPK1, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, MAPKAPK2, NFATC2, NRAS,
PIK3CA, PIK3CB, PIK3CD, PLCG1, PLCG2, PPP3CA, PPP3CB, PPP3CC, PPP3R1, PPP3R2, PRKCA, PRKCB, PTGS2, PTK2, PXN, RAC1, RAC2, RAC3, RAF1, SRC,
VEGFA
Viral protein interaction with cytokine and cytokine receptor ACKR3, CCL1, CCL11, CCL13, CCL19, CCL2, CCL21, CCL24, CCL25, CCL26, CCL3, CCL3L3, CCL4, CCL5, CCL7, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7,
(hsa04061) CCR8, CCR9, CSF1, CSF1R, CX3CL1, CX3CR1, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL2, CXCL3, CXCL5, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3,
CXCR4, CXCR5, IL10, IL10RA, IL10RB, IL18, IL18R1, IL18RAP, IL19, IL2, IL20, IL20RA, IL20RB, IL22RA1, IL24, IL2RA, IL2RB, IL2RG, IL6, IL6R, IL6ST, LTA, LTBR,
PF4, PPBP, TNF, TNFRSF14, TNFRSF1A, TNFRSF1B, TNFSF10, TNFSF14, XCR1

Supplementary Table S3. SLE case-control pathway based aggregate association analysis result (SKAT-O).
Ratio genes on
Genes in Genes on array/ genes in SNVs in
Pathway (KEGG ID) pathway array pathway test P-value FDR
Th1 and Th2 cell differentiation (hsa04658) 92 78 0.85 14362 6.3E-11 2.2E-09
Antigen processing and presentation (hsa04612) 77 40 0.52 8017 1.8E-10 3.1E-09
Hematopoietic cell lineage (hsa04640) 97 71 0.73 13013 3.8E-10 4.5E-09
Th17 cell differentiation (hsa04659) 107 96 0.90 19347 1.7E-09 1.5E-08
Intestinal immune network for IgA production (hsa04672) 49 39 0.80 7909 3.4E-08 2.4E-07
Natural killer cell mediated cytotoxicity (hsa04650) 131 100 0.76 15821 4.7E-06 2.8E-05
TNF signaling pathway (hsa04668) 112 88 0.79 12639 1.9E-05 9.4E-05
JAK-STAT signaling pathway (hsa04630) 162 133 0.82 18003 7.4E-05 0.00032
RIG-I-like receptor signaling pathway (hsa04622) 70 63 0.90 8459 0.00021 0.00080
NOD-like receptor signaling pathway (hsa04621) 178 109 0.61 15729 0.00031 0.0011
Complement and coagulation cascades (hsa04610) 79 50 0.63 7112 0.00041 0.0013
Toll-like receptor signaling pathway (hsa04620) 104 96 0.92 12178 0.00080 0.0022
Cytokine-cytokine receptor interaction (hsa04060) 294 221 0.75 26771 0.00083 0.0022
C-type lectin receptor signaling pathway (hsa04625) 104 75 0.72 12986 0.0020 0.0050
IL-17 signaling pathway (hsa04657) 93 68 0.73 9358 0.0043 0.0100
Fc epsilon RI signaling pathway (hsa04664) 68 51 0.75 8514 0.0052 0.011
Viral protein interaction with cytokine and cytokine receptor
(hsa04061) 100 75 0.75 8435 0.0062 0.013
NF-kappa B signaling pathway (hsa04064) 102 88 0.86 14349 0.0078 0.015
Osteoclast differentiation (hsa04380) 128 101 0.79 18602 0.013 0.023
T cell receptor signaling pathway (hsa04660) 103 85 0.83 14268 0.014 0.025
Cytosolic DNA-sensing pathway (hsa04623) 63 40 0.63 4993 0.015 0.025
B cell receptor signaling pathway (hsa04662) 82 61 0.74 11330 0.037 0.059
HIF-1 signaling pathway (hsa04066) 109 60 0.55 11748 0.043 0.065
Fc gamma R-mediated phagocytosis (hsa04666) 94 48 0.51 9608 0.055 0.080
Apoptosis (hsa04210) 136 78 0.57 12115 0.066 0.092
Prolactin signaling pathway (hsa04917) 70 51 0.73 7599 0.15 0.20
MAPK signaling pathway (hsa04010) 295 151 0.51 27384 0.16 0.20
Chemokine signaling pathway (hsa04062) 190 111 0.58 15084 0.16 0.20
Neurotrophin signaling pathway (hsa04722) 119 70 0.59 12388 0.18 0.22
VEGF signaling pathway (hsa04370) 59 39 0.66 7440 0.19 0.22
ErbB signaling pathway (hsa04012) 85 54 0.64 11201 0.28 0.31
FoxO signaling pathway (hsa04068) 132 67 0.51 10643 0.29 0.31
Adherens junction (hsa04520) 72 42 0.58 9633 0.29 0.31
Apoptosis - multiple species (hsa04215) 33 20 0.61 3722 0.31 0.32
Leukocyte transendothelial migration (hsa04670) 112 64 0.57 11444 0.35 0.35
FDR: False Discovery Rate

Supplementary Table S4. Pathway SLE polygenic risk scores, SLE patients positive for each pathway. The
threshold for the pathway PRS was set at the 97.5th percentile in control individuals.
N SLE SNVs N patients Percent patients

Pathway name (KEGG ID) in PRS positive positive
Cytokine-cytokine receptor interaction (hsa04060) 297 390 40.7%
Osteoclast differentiation (hsa04380) 200 336 35.1%
MAPK signaling pathway (hsa04010) 263 333 34.8%
Jak-STAT signaling pathway (hsa04630) 214 276 28.8%
Chemokine signaling pathway (hsa04062) 158 256 26.7%
TNF signaling pathway (hsa04668) 144 247 25.8%
NF-kappa B signaling pathway (hsa04064) 157 246 25.7%
T cell receptor signaling pathway (hsa04660) 160 230 24.0%
Neurotrophin signaling pathway (hsa04722) 124 227 23.7%
HIF-1 signaling pathway (hsa04066) 113 223 23.3%
NOD-like receptor signaling pathway (hsa04621) 161 219 22.9%
Toll-like receptor signaling pathway (hsa04620) 138 212 22.1%
C-type lectin receptor signaling pathway (hsa04625) 136 209 21.8%
Complement and coagulation cascades (hsa04610) 73 198 20.7%
Th17 cell differentiation (hsa04659) 227 196 20.5%
Apoptosis (hsa04210) 118 190 19.8%
Leukocyte transendothelial migration (hsa04670) 106 190 19.8%
Hematopoietic cell lineage (hsa04640) 145 175 18.3%
Natural killer cell mediated cytotoxicity (hsa04650) 194 174 18.2%
Th1 and Th2 cell differentiation (hsa04658) 187 174 18.2%
B cell receptor signaling pathway (hsa04662) 128 172 18.0%
IL-17 signaling pathway (hsa04657) 102 171 17.8%
ErbB signaling pathway (hsa04012) 107 169 17.6%
RIG-I-like receptor signaling pathway (hsa04622) 91 158 16.5%
FoxO signaling pathway (hsa04068) 119 157 16.4%
Prolactin signaling pathway (hsa04917) 85 153 16.0%
Fc epsilon RI signaling pathway (hsa04664) 98 149 15.6%
Antigen processing and presentation (hsa04612) 127 149 15.6%
Fc gamma R-mediated phagocytosis (hsa04666) 107 143 14.9%
Viral protein interaction with cytokine and cytokine receptor
(hsa04061) 96 143 14.9%
Adherens junction (hsa04520) 87 142 14.8%
VEGF signaling pathway (hsa04370) 81 133 13.9%
Cytosolic DNA-sensing pathway (hsa04623) 40 124 12.9%
Intestinal immune network for IgA production (hsa04672) 106 117 12.2%
Apoptosis - multiple species (hsa04215) 41 91 9.5%

Supplementary Table S5. Analysed gene-sets and their genes. Only sequenced genes are listed.
Gene set Genes (RefSeq) References

Interferon DDX58, IFI16, IFIH1, IFNA1, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA2, Rönnblom & Leonard, 2019 (PMID:31497305)
IFNA21, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNAR1, IFNAR2, IFNB1, IFNE, IFNK,
IFNW1, IRF5, IRF7, IRF9, JAK1, MAVS, PRKDC, STAT1, STAT2, STAT4, TYK2, ZBP1
Interferonopathy ACP5, ADAR, C1QA, C1QB, C1QC, COPA, DDX58, IFIH1, ISG15, PSMB8, TREX1 Rodero & Crow, 2016 (PMID:27821552); Rodero et al., 2017
(PMID:29259162); Davidson et al., 2018 (PMID:29846818)
SLE GWAS ABHD6, ATXN2, BACH2, BANK1, BLK, CD226, CD40, CD44, CD80, CDKN1B, CIITA, Chen et al., 2017 (PMID:28509669); Langefeld et al., 2017
CLEC16A, CSK, CXCR5, ELF1, ETS1, EVI5, FAM167A, FAM98B, FCGR2A, GALC, GRAP2, (PMID:28714469)
GRB2, GTF2I, HCFC1, HIC2, HIP1, HLA-B, HLA-C, HLA-DQA1, HLA-DQA2, HLA-DRB1,
ICAM1, IFIH1, IFNLR1, IKBKE, IKZF1, IKZF3, IL10, IL12A, IL12B, IL12RB2, IL21, IRAK1,
IRF5, IRF7, IRF8, JAK2, LBH, LPP, LYN, LYST, MICB, MSH5, NCF2, NFKBIA, NOTCH2,
NOTCH4, OLIG3, PHRF1, PLAT, PRDM1, PTPN22, PTPRC, PTTG1, PXK, RAD51B,
RASGRP1, RASGRP3, RNF114, SH2B3, SLC15A4, SOCS1, SPRED2, STAT4, TCF7, TLR7,
TNFAIP3, TNFSF4, TNIP1, TNPO3, TNXB, TRAFD1, TYK2, UBE2L3, WDFY4, YDJC,
ZFP90
Complement C1QA, C1QB, C1QC, C1R, C1S, C2, C3, C3AR1, C4A, C4B, C4BPA, C5, C5AR1, C6, C7, Complement subset of the KEGG Complement and coagulation
C9, CD46, CD55, CD59, CFB, CFD, CFH, CFI, CR1, CR2, ITGAM, ITGAX, ITGB2, MASP1, cascades pathway (hsa04610)
MASP2, MBL2, SERPING1
Monogenic SLE ACP5, ADAR, C1QA, C1QB, C1QC, C1R, C1S, C2, C3, C4A, C4B, CYBB, DDX58, Tsokos et al., 2016 (PMID:27872476)
DNASE1L3, FAS, FASLG, IFIH1, ISG15, PRKCD, PSMB8, PTPN11, RAG1, RAG2, TREX1

Supplementary Table S6. Top gene regions from aggregate testing (SKAT-O). Potentially novel loci are indicated in bold and
only gene regions with FDR 0.05 or less are listed.
Non-
Gene N Conserved
Chr Start bp End bp synonymous Top SNV
d
FDR P-value
regiona variants b variantsc
variants
TNXB 6 31908832 32177251 362 43 102 rs369580 1.7E-13 9.1E-17
PABPC4 1 39926385 40142621 132 10 45 rs879037 6.6E-06 4.3E-08
IFNK 9 27424212 27626596 231 7 58 rs895023 0.00081 1.2E-05
ATF2 2 175836878 176133034 166 4 64 rs79907460 0.0091 0.00016
SLC30A6 2 32290810 32549548 160 14 33 rs2365556 0.025 0.00048
SERPING1 11 57264927 57482426 167 14 42 rs12801093 0.04 0.0008
SRD5A2 2 31649556 31906140 48 0 3 rs28383069 0.04 0.00083
SPAST 2 32188580 32482806 190 12 31 rs2365556 0.042 0.0009
MEMO1 2 31992779 32336221 110 0 21 rs533970 0.046 0.0011
Only the top gene in the extended MHC on chr 6 is listed. Associations surviving Bonferroni correction for multiple testing (1832 gene
regions) are above the line (P<2.7E-05). a) Gene regions included ±100kb to cover targeted regulatory regions; b) missense or nonsense
variants; c) constrained variants defined as GERP RS score >2; d) Top associated SNV from the SLE case-control single variant logistic
regression analysis. Bp: base pair, SNV: single nucleotide variant, FDR: False Discovery Rate.

Supplementary Table 7. Top gene regions from SLE case-control aggregate association testing
including functional annotation (GenePy). Gene regions with P-values surviving permutation
testing are listed.
Gene region Chr Start BP End BP SNVs in test Annotation P-value

MSH5 6 31706725 31731455 11 CADD 4.6E-15
CYP21A2 6 32005093 32010447 23 CADD 4.4E-12
TNXB 6 32007932 32078151 69 CADD 1.4E-11
HLA-DOB 6 32779540 32785825 74 CADD 7.2E-11
AGER 6 32147745 32153099 29 CADD 1.6E-10
HLA-DQB2 6 32722837 32732330 65 CADD 2.5E-09
MICA 6 31366561 31384090 196 CADD 2.3E-08
NOTCH4 6 32161620 32192844 120 CADD 2.7E-08
BTNL2 6 32361513 32375900 34 CADD 1.8E-07
BANK1 4 102710764 102996969 227 CADD 8.2E-07
HLA-C 6 31235526 31240913 169 CADD 9.5E-07
IRF5 7 128576976 128591089 44 CADD 2.2E-06
CFB 6 31912721 31920861 33 CADD 1.1E-05
HLA-DQA1 6 32604169 32613152 512 CADD 1.5E-05
MICB 6 31461054 31479901 13 REVEL 6.6E-24
TAP2 6 32788610 32807547 15 REVEL 1.1E-09
HLA-C 6 31235526 31240913 15 REVEL 5.8E-08
BTNL2 6 32361513 32375900 35 REVEL 3.5E-07
HLA-DQB1 6 32626241 32635466 18 REVEL 4.1E-06
CFB 6 31912721 31920861 14 REVEL 2.0E-05
MICA 6 31366561 31384090 26 REVEL 2.2E-05
BANK1 4 102710764 102996969 16 REVEL 3.4E-05
SLC15A4 12 129276739 129309541 5 REVEL 4.0E-05
HLA-B 6 31320649 31325989 12 REVEL 6.9E-05
CADD: weights including 63 annotations, such as conservation metrics, functional genomic data,
transcript information and protein level scores;
REVEL: weights based on pathogenicity of rare missense variants.

Supplementary Table S8. Single variant SLE case-control association results Swedish cohort, independent loci with P<1x10-4.
CHR BP SNV Locus Minor/major allele MAF case MAF control OR FDR P
6 31708463 rs3131381 MSH5 A/C 0.248 0.113 2.82 6.2E-23 6.7E-28
6 32612110 rs9273058 HLA-DQA1 C/T 0.339 0.504 0.49 2.9E-20 1.3E-23
6 31464798 rs2534675 MICB T/C 0.449 0.292 2.02 6.0E-20 3.2E-23
7 128695983 rs13239597 IRF5/TNPO3 A/C 0.238 0.143 1.88 4.1E-11 1.1E-13
1 183542323 rs17849501 NCF2 T/C 0.108 0.053 2.33 3.3E-09 1.6E-11
2 191925424 rs3024859 STAT4 T/C 0.279 0.199 1.54 2.1E-06 1.4E-08
7 50308692 rs876037 IKZF1 A/T 0.242 0.312 0.66 3.4E-06 2.3E-08
16 11198932 rs35300161 CLEC16A T/C 0.133 0.188 0.63 0.00013 1.2E-06
2 191919354 rs11676659 STAT4 G/A 0.033 0.063 0.46 0.00018 1.6E-06
6 106594719 rs2179175 PRDM1 T/C 0.278 0.222 1.44 0.00036 3.5E-06
9 27483959 rs895023 MOB3B/IFNK G/A 0.026 0.056 0.45 0.00065 6.9E-06
12 129294244 rs11059926 SLC15A4 T/A 0.132 0.084 1.60 0.00088 9.5E-06
12 96374683 rs6538696 HAL T/C 0.533 0.467 1.34 0.0013 1.4E-05
2 30961022 rs55799526 CAPN13 G/C 0.057 0.094 0.58 0.0018 2.1E-05
4 102340309 rs10433984 BANK1 A/T 0.301 0.250 1.37 0.0026 3.0E-05
5 150442171 rs3792790 TNIP1 C/A 0.459 0.529 0.75 0.0027 3.2E-05
6 138230040 rs200820567 TNFAIP3 A/T 0.061 0.035 1.89 0.0034 4.2E-05
10 64427649 rs7075349 ZNF365/EGR2 G/A 0.311 0.372 0.75 0.0041 5.0E-05
6 15168274 rs9396569 JARID2 A/G 0.143 0.107 1.48 0.0057 7.2E-05
19 10526854 rs34953890 CDC37/TYK2 A/C 0.170 0.220 0.71 0.0070 9.2E-05
10 128935768 rs12263483 DOCK1/FAM196A G/A 0.101 0.142 0.67 0.0075 9.9E-05
Top SNP (or SNPs if independent) from each locus with at least one variant with P<1x10-4
Loci forwarded for replication are indcated in bold

Supplementary Table S9. Single variant SLE case-control association analysis in the Norwegian and Danish replication cohorts, and Sandinavian
cohorts meta-analysis.
Norway Denmark Meta-analysis Scandinavia

MAF MAF Odds MAF MAF Odds P- Odds P-value
2
CHR BP SNV Gene region SLE Ctrl ratio P-value SLE Ctrl ratio value ratio (R) (R) Q I
2 30957326 rs2276568 CAPN13 0.081 0.063 1.32 0.19 0.080 0.061 1.33 0.067 1.03 0.93 0.00010 89
2 30961022 rs55799526 CAPN13 0.081 0.061 1.38 0.13 0.081 0.061 1.37 0.045 1.05 0.85 0.00010 90
2 30964632 rs72783018 CAPN13 0.087 0.064 1.37 0.12 0.075 0.063 1.22 0.21 1.06 0.74 0.012 77
2 30967587 rs72783020 CAPN13 0.087 0.063 1.41 0.093 0.078 0.063 1.27 0.13 1.08 0.70 0.0045 81
9 27482627 rs4879517 MOB3B 0.052 0.042 1.25 0.39 0.047 0.036 1.30 0.18 0.90 0.77 0 90
9 27483959 rs895023 MOB3B 0.052 0.051 1.01 0.96 0.047 0.037 1.26 0.23 0.83 0.58 0.00020 88
9 27489047 rs78313606 MOB3B 0.047 0.041 1.15 0.59 0.034 0.033 1.04 0.87 0.82 0.49 0.0034 82
9 27489418 rs76324761 MOB3B 0.047 0.041 1.15 0.59 0.034 0.033 1.04 0.87 0.82 0.49 0.0032 83
9 27498800 rs1031154 IFNK/MOB3B 0.054 0.042 1.30 0.30 0.046 0.038 1.21 0.32 0.91 0.78 0.00030 88
9 27502986 rs1977661 IFNK/MOB3B 0.087 0.092 0.93 0.70 0.088 0.092 0.95 0.70 0.96 0.63 0.96 0
12 96374750 rs2270318 HAL 0.39 0.36 1.16 0.18 0.42 0.41 1.05 0.54 1.15 0.0014 0.39 0
Top SLE associated SNVs from the Swedish SLE case-control cohort are indicated in bold. The the top SNV in HAL (rs6538696) failed genotyping.
Scandinavia meta-analysis included 1,794 SLE patients and 3,241 control individuals from Sweden, Norway and Denmark.
Random-effects meta-analysis (R) p-values and odds ratio estimates are shown.
MAF= Minor allele frequency, Q= P-value for Cochran's Q statistic, I2= I2 heterogeneity index (0-100 scale).

Supplementary Table S10. Rare non-synonymous variants in genes for monogenic SLE and lupus-like disease.
SLE (N=958) Controls (N=1026)
Minor Count Count Minor Count Count

allele homozygous hetero- allele homozygous hetero-
CHR BP SNV REF ALT Gene name Consequence Amino acid change count MAF allele 1 zygotes count MAF allele 1 zygotes
1 22965341 rs772544683 G A C1QA missense variant p.Arg60Gln 0 0 0 0 1 0.00051 0 1
1 22973825 chr1:22973825 C G C1QC missense variant p.Pro96Arg 1 0.00056 0 1 0 0 0 0
1 22974053 rs560156356 C T C1QC missense variant p.Ala172Val 1 0.00056 0 1 0 0 0 0
1 154557500 chr1:154557500 G A ADAR missense variant p.Arg1198Trp 0 0 0 0 1 0.00049 0 1
1 154562881 rs145849344 C T ADAR missense variant p.Val802Ile 0 0 0 0 1 0.00049 0 1
1 154570903 rs17843865 T C ADAR missense variant p.Tyr630Cys 1 0.00052 0 1 0 0 0 0
1 154571009 rs771516546 C T ADAR missense variant p.Gly595Arg 0 0 0 0 1 0.00049 0 1
1 154573655 rs748585963 G C ADAR missense variant p.Pro531Arg 0 0 0 0 1 0.00049 0 1
1 154575074 chr1:154575074 T G ADAR missense variant p.His58Pro 0 0 0 0 1 0.00049 0 1
1 154600474 rs186420937 T C ADAR start lost p.Met1? 4 0.0021 0 4 3 0.0015 0 3
2 163124024 rs144455277 G C IFIH1 missense variant p.Gln955Glu 2 0.0010 0 2 5 0.0024 0 5
2 163128887 rs376048533 C T IFIH1 missense variant p.Arg822Gln 1 0.00052 0 1 0 0 0 0
2 163133396 rs72650663 G A IFIH1 missense variant p.Thr702Ile 4 0.0021 0 4 1 0.00049 0 1
2 163134054 rs774347658 C T IFIH1 missense variant p.Ala639Thr 1 0.00052 0 1 0 0 0 0
2 163134090 rs35744605 C A IFIH1 stop gained p.Glu627* 8 0.0042 0 8 9 0.0044 0 9
2 163134176 rs200945986 C T IFIH1 missense variant p.Arg598His 0 0 0 0 1 0.00049 0 1
2 163136564 rs142348767 A C IFIH1 missense variant p.Leu528Arg 1 0.00052 0 1 0 0 0 0
2 163137999 rs772981550 T C IFIH1 missense variant p.Asn455Asp 0 0 0 0 2 0.00097 0 2
2 163138050 rs139714761 A G IFIH1 missense variant p.Ser438Pro 0 0 0 0 1 0.00049 0 1
2 163144659 rs775244788 C T IFIH1 missense variant p.Val361Ile 1 0.00052 0 1 0 0 0 0
2 163144674 rs150317197 G T IFIH1 missense variant p.Pro356Thr 1 0.00052 0 1 1 0.00049 0 1
2 163144694 rs72650664 T C IFIH1 missense variant p.Lys349Arg 4 0.0021 0 4 0 0 0 0
2 163163228 chr2:163163228 C T IFIH1 missense variant p.Val254Ile 1 0.00052 0 1 0 0 0 0
2 163167419 rs74162075 T C IFIH1 missense variant p.Asn160Asp 2 0.0011 0 2 4 0.0020 0 4
2 163174487 rs760903088 G T IFIH1 missense variant p.His111Asn 1 0.00052 0 1 0 0 0 0
2 163174615 chr2:163174615 T C IFIH1 missense variant p.Lys68Arg 1 0.00053 0 1 0 0 0 0
3 48508028 rs749323787 G A TREX1 missense variant p.Gly47Ser 1 0.00056 0 1 0 0 0 0
3 48508962 rs765487310 C T TREX1 missense variant p.Thr358Ile 1 0.00053 0 1 0 0 0 0
3 53213596 rs376358631 G A PRKCD missense variant p.Arg40His 1 0.00055 0 1 0 0 0 0
3 53217499 chr3:53217499 C T PRKCD missense variant p.Pro230Leu 1 0.00055 0 1 0 0 0 0
3 53223210 rs146289210 C T PRKCD missense variant p.Thr564Met 1 0.00054 0 1 1 0.00050 0 1
3 58179012 rs766661698 C T DNASE1L3 missense variant p.Ala287Thr 1 0.00052 0 1 1 0.00049 0 1
3 58191230 rs12491947 G T DNASE1L3 missense variant p.Asn96Lys 9 0.0047 0 9 5 0.0024 0 5
3 58191274 rs74350392 C G DNASE1L3 missense variant p.Gly82Arg 8 0.0042 0 8 13 0.0063 0 13
6 31901976 rs150827255 C G C2 missense variant p.Ser250Cys 1 0.00052 0 1 0 0 0 0

6 31911055 rs142243595 G A C2 missense variant p.Ala472Thr 0 0 0 0 1 0.00049 0 1

6 31912523 rs36221133 T C C2 missense variant p.Val641Ala 10 0.0052 0 10 17 0.0083 0 17
6 31996241 rs764056735 G A C4B missense variant p.Met1054Ile 0 0 0 0 2 0.0010 1 0
6 31996773 rs781626894 A G C4B missense variant p.Ile1147Val 0 0 0 0 1 0.00050 0 1
6 32810551 chr6:32810551 C A PSMB8 missense variant p.Arg102Leu 0 0 0 0 1 0.00049 0 1
6 32810794 rs17220206 T A PSMB8 missense variant p.Thr74Ser 2 0.0010 0 2 1 0.00049 0 1
9 32457245 rs138425677 G A DDX58 missense variant p.Pro885Ser 3 0.0016 0 3 0 0 0 0
9 32472997 rs139726764 G A DDX58 missense variant p.Arg664Cys 1 0.00053 0 1 0 0 0 0
9 32480284 chr9:32480284 G C DDX58 missense variant p.Asp569Glu 1 0.00052 0 1 0 0 0 0
missense variant &
9 32481339 rs61752945 C T DDX58 splice region variant p.Arg546Gln 11 0.0057 0 11 14 0.0068 0 14
9 32500832 rs72710678 C T DDX58 missense variant p.Arg71His 22 0.011 0 22 13 0.0063 0 13
9 32526076 rs147964586 G A DDX58 missense variant p.Ala30Val 1 0.00052 0 1 0 0 0 0
10 90771767 rs56006128 G A FAS missense variant p.Glu194Lys 4 0.0022 0 4 1 0.00050 0 1
11 36595579 rs76897604 A G RAG1 missense variant p.Gln242Arg 14 0.0073 0 14 17 0.0084 0 17
11 36596695 chr11:36596695 G A RAG1 missense variant p.Ser614Asn 0 0 0 0 1 0.00049 0 1
11 36597492 rs4151033 G A RAG1 missense variant p.Glu880Lys 5 0.0026 0 5 0 0 0 0
11 36597513 rs4151034 G A RAG1 missense variant p.Asp887Asn 10 0.0052 0 10 13 0.0064 1 11
11 36597870 rs139113046 A G RAG1 missense variant p.Met1006Val 11 0.0057 0 11 15 0.0073 0 15
11 36614202 rs144812762 C T RAG2 missense variant p.Arg506His 0 0 0 0 1 0.00049 0 1
11 36614521 rs140682926 C G RAG2 missense variant p.Asp400His 1 0.00052 0 1 7 0.0034 0 7
11 36614574 chr11:36614574 T G RAG2 missense variant p.Glu382Ala 0 0 0 0 1 0.00049 0 1
11 36614910 rs149241274 T C RAG2 missense variant p.Glu270Gly 1 0.00052 0 1 0 0 0 0
11 65487283 chr11:65487283 G C RNASEH2C missense variant p.Ala234Gly 1 0.00053 0 1 0 0 0 0
11 65487341 chr11:65487341 T C RNASEH2C missense variant p.Met215Val 1 0.00053 0 1 0 0 0 0
11 65487503 rs182000627 C T RNASEH2C missense variant p.Gly161Arg 3 0.0017 0 3 0 0 0 0
11 65487511 rs753880827 C G RNASEH2C missense variant p.Ser158Thr 1 0.00056 0 1 0 0 0 0
12 7173211 rs781960849 A G C1S missense variant p.Ile270Val 1 0.00052 0 1 0 0 0 0
12 7173893 rs117907409 G A C1S missense variant p.Asp315Asn 3 0.0016 0 3 6 0.0029 0 6
12 7175028 rs20573 G A C1S missense variant p.Arg383His 2 0.0010 0 2 0 0 0 0
12 7175824 rs139493862 A C C1S missense variant p.Lys420Asn 0 0 0 0 1 0.00049 0 1
12 7177488 rs121909582 C T C1S missense variant p.Arg534Trp 1 0.00052 0 1 0 0 0 0
12 7241211 rs117402032 T G C1R missense variant p.Ile344Leu 1 0.00052 0 1 0 0 0 0
12 7242740 rs139531404 C G C1R missense variant p.Met111Ile 5 0.0026 0 5 10 0.0049 0 10
16 3705479 rs34907394 G C DNASE1 missense variant p.Glu35Asp 6 0.0034 0 6 3 0.0016 0 3
16 3705900 rs755091005 C G DNASE1 missense variant p.His66Gln 1 0.0006 0 1 0 0 0 0
missense variant &
16 3706754 chr16:3706754 G C DNASE1 splice region variant p.Glu146Gln 0 0 0 0 1 0.00051 0 1
16 3707066 rs150933932 C T DNASE1 missense variant p.Ala168Val 5 0.0028 0 5 7 0.0036 0 7
16 3707191 rs74892550 G A DNASE1 missense variant p.Val185Ile 0 0 0 0 11 0.0056 0 11
missense variant &
16 3707341 rs139254891 A T DNASE1 splice region variant p.Arg235Trp 1 0.00056 0 1 0 0 0 0

19 6678454 rs778590435 C T C3 missense variant p.Arg1548Gln 1 0.00054 0 1 0 0 0 0

19 6697719 rs771305132 C T C3 missense variant p.Glu843Lys 1 0.00053 0 1 0 0 0 0
19 6711182 rs532944249 G A C3 missense variant p.Ser432Leu 0 0 0 0 1 0.00052 0 1
19 6719341 rs780548430 G C C3 missense variant p.Gln50Glu 1 0.00057 0 1 0 0 0 0
19 11685942 rs147115345 G A ACP5 missense variant p.Thr45Ile 1 0.00055 0 1 3 0.0015 0 3
19 11685989 rs147025508 G A ACP5 missense variant p.Arg272Cys 10 0.0055 0 10 7 0.0036 0 7
19 11686037 rs146196342 C G ACP5 missense variant p.Val256Leu 2 0.0011 0 2 1 0.00051 0 1
19 11687621 rs141651325 C T ACP5 missense variant p.Arg100His 0 0 0 0 1 0.00051 0 1
19 11687630 rs777140546 C T ACP5 missense variant p.Arg97His 0 0 0 0 1 0.00051 0 1
19 11688072 rs757630659 C G ACP5 missense variant p.Gly21Arg 1 0.00057 0 1 0 0 0 0
19 12918104 rs754727728 T C RNASEH2A missense variant p.Val95Ala 0 0 0 0 1 0.00049 0 1
19 12920928 rs757486362 G A RNASEH2A missense variant p.Arg152Gln 0 0 0 0 2 0.00098 0 2
19 12921196 rs62619782 T A RNASEH2A missense variant p.Asp205Glu 12 0.0063 0 12 8 0.0039 0 8
missense variant &
19 12921216 rs377244188 A T RNASEH2A splice region variant p.Asn212Ile 1 0.00052 0 1 2 0.00098 0 2
19 12923974 rs372667206 C T RNASEH2A missense variant p.Arg239Cys 1 0.00053 0 1 2 0.00097 0 2
X 37658266 chrX:37658266 G A CYBB missense variant p.Glu245Lys 0 0 0 0 1 0.00053 0 1
X 37663322 rs141756032 G C CYBB missense variant p.Gly364Arg 8 0.0045 0 8 9 0.0048 0 9
MAF: Minor Allele Frequency

Supplementary Table S11. SLE case-only non-synonymous variants. These are missense or nonsense SNVs observed in at least one SLE patient, but
not in the control population or in external sets of control individuals of similar ancestry (SweGen and GnomAD: European non-Finnish controls;
Ameur et al. 2017, Karczewski et al. 2019)
SLE (n=958)
Minor
Minor Major allele Minor allele Amino acid
CHR BP SNV allele allele count frequency Gene name Consequence change
11 1266280 rs773068050 C A 5 0.0028 MUC5B missense variant p.Thr2727Pro
1 186363103 chr1:186363103 A C 4 0.0023 C1orf27 missense variant p.Gln246Lys
1 151342270 rs772030489 T G 2 0.0011 SELENBP1 missense variant p.Pro36Thr
2 27455971 rs776014297 A T 2 0.0010 CAD missense variant p.Met922Lys
2 179698928 chr2:179698928 A G 2 0.0010 CCDC141 missense variant p.Ser1522Phe
9 16431447 chr9:16431447 A G 2 0.0011 BNC2 missense variant p.His307Tyr
9 21166175 rs779242420 C T 2 0.0010 IFNA21 missense variant p.Tyr146Cys
10 75583821 chr10:75583821 T G 2 0.0011 CAMK2G missense variant p.His370Asn
12 6458353 rs775543049 A G 2 0.0010 SCNN1A stop gained p.Arg551*
12 48482728 rs750735162 C T 2 0.0010 SENP1 missense variant p.Thr79Ala
12 56350882 chr12:56350882 T G 2 0.0010 PMEL missense variant p.Pro402His
12 129190793 chr12:129190793 G C 2 0.0011 TMEM132C missense variant p.Pro1094Ala
14 23057866 chr14:23057866 T A 2 0.0010 DAD1 missense variant p.Ser66Arg
15 91030272 rs181919733 A G 2 0.0010 IQGAP1 missense variant p.Val1371Met
17 41143320 chr17:41143320 A G 2 0.0011 RUNDC1 missense variant p.Val477Ile
19 4891395 rs139019426 C T 2 0.0010 ARRDC5 missense variant p.Gln231Arg
19 18273781 rs777121279 A G 2 0.0011 PIK3R2 missense variant p.Gly372Ser
missense variant &
19 55240959 rs764066889 A G 2 0.0010 KIR3DL3 splice region variant p.Gly219Asp
1 905700 rs759355675 G C 1 0.00056 PLEKHN1 missense variant p.Pro76Arg
stop gained & splice
1 1246066 chr1:1246066 T C 1 0.00055 PUSL1 region variant p.Gln233*
1 3739745 rs148840465 T C 1 0.00052 CEP104 missense variant p.Gly855Glu
1 6529607 rs781318885 C G 1 0.00055 PLEKHG5 missense variant p.Pro723Ala
1 6535129 chr1:6535129 A C 1 0.00055 PLEKHG5 missense variant p.Ala173Ser
1 6589075 rs147263684 C T 1 0.00052 NOL9 missense variant p.Ile602Val
1 7798073 rs778503877 G A 1 0.00052 CAMTA1 missense variant p.Lys1238Arg
1 7812557 rs369220323 A G 1 0.00052 CAMTA1 missense variant p.Arg1641Gln
1 7837316 chr1:7837316 T G 1 0.00052 VAMP3 missense variant p.Ala57Ser
1 7879456 chr1:7879456 C T 1 0.00052 PER3 missense variant p.Ile545Thr
1 8075450 chr1:8075450 G A 1 0.00052 ERRFI1 missense variant p.Phe46Leu
1 8399719 chr1:8399719 T G 1 0.00053 SLC45A1 missense variant p.Leu681Phe
1 8424007 rs778046482 C T 1 0.00056 RERE missense variant p.Lys134Glu
1 9786994 chr1:9786994 A G 1 0.00052 PIK3CD missense variant p.Glu1033Lys
1 10195185 rs138056371 G A 1 0.00052 UBE4B missense variant p.Asn722Ser
1 10386339 rs141942131 T C 1 0.00052 KIF1B missense variant p.Thr949Met
1 10523664 chr1:10523664 A G 1 0.00054 DFFA missense variant p.Ala152Val
1 11090845 chr1:11090845 C G 1 0.00052 MASP2 stop gained p.Tyr394*
1 11169772 chr1:11169772 G C 1 0.00052 MTOR missense variant p.Val2461Leu
1 11255025 chr1:11255025 G C 1 0.00052 ANGPTL7 missense variant p.Thr329Ser
1 12336842 chr1:12336842 A T 1 0.00052 VPS13D missense variant p.Val1066Asp
1 12337649 chr1:12337649 C A 1 0.00052 VPS13D missense variant p.Glu1335Ala
1 12359263 chr1:12359263 A G 1 0.00052 VPS13D missense variant p.Arg2013Lys
1 15855646 chr1:15855646 A C 1 0.00052 DNAJC16 missense variant p.Leu16Met
1 15892647 rs61738974 A G 1 0.00052 DNAJC16 missense variant p.Glu584Lys
1 16260959 chr1:16260959 C A 1 0.00057 SPEN missense variant p.Thr2742Pro
1 17277609 rs757471392 T C 1 0.00053 CROCC missense variant p.Arg1000Cys
1 19566385 chr1:19566385 A T 1 0.00052 EMC1 missense variant p.His294Leu
1 21952859 rs768044335 C G 1 0.00052 RAP1GAP missense variant p.Gln38Glu
1 22062929 chr1:22062929 G A 1 0.00052 USP48 missense variant p.Phe109Ser
1 22078025 chr1:22078025 A G 1 0.00052 USP48 missense variant p.Thr250Ile
1 22329533 chr1:22329533 A C 1 0.00054 CELA3A missense variant p.Ser27Arg
1 22973825 chr1:22973825 G C 1 0.00056 C1QC missense variant p.Pro96Arg
1 24409181 rs148441250 A G 1 0.00052 MYOM3 missense variant p.Thr666Met
1 24484263 chr1:24484263 T C 1 0.00053 IFNLR1 missense variant p.Arg307Gln
1 25166361 chr1:25166361 C G 1 0.00052 CLIC4 missense variant p.Arg142Ser
1 26784313 chr1:26784313 T C 1 0.00052 DHDDS missense variant p.Leu192Phe
1 26870645 chr1:26870645 G C 1 0.00052 RPS6KA1 missense variant p.Pro47Arg
1 26900915 rs755547404 A G 1 0.00054 RPS6KA1 missense variant p.Cys110Tyr
1 27734810 rs200665850 T C 1 0.00052 WASF2 missense variant p.Arg457Gln
1 32098045 chr1:32098045 A G 1 0.00055 HCRTR1 missense variant p.Glu366Lys

1 40038204 chr1:40038204 T C 1 0.00052 PABPC4 missense variant p.Arg83His

1 40125028 chr1:40125028 T C 1 0.00056 NT5C1A missense variant p.Arg291Gln
1 43719800 chr1:43719800 T G 1 0.00052 WDR65 missense variant p.Ala1231Ser
1 43886632 chr1:43886632 A C 1 0.00052 SZT2 missense variant p.Arg492Ser
1 43907384 chr1:43907384 G C 1 0.00053 SZT2 missense variant p.Ala2489Gly
1 52840492 rs767782494 A G 1 0.00052 ORC1 missense variant p.Thr794Met
1 52902547 chr1:52902547 G C 1 0.00052 ZCCHC11 missense variant p.Asp1348His
1 57378187 chr1:57378187 T C 1 0.00057 C8A stop gained p.Arg498*
1 57537275 chr1:57537275 T G 1 0.00052 DAB1 missense variant p.Leu160Ile
1 59156063 rs768128851 A G 1 0.00057 MYSM1 missense variant p.Pro82Leu
1 61554274 chr1:61554274 G C 1 0.00052 NFIA missense variant p.Leu206Val
1 61554329 chr1:61554329 G T 1 0.00052 NFIA missense variant p.Leu224Trp
1 63870189 chr1:63870189 G A 1 0.00052 ALG6 missense variant p.His108Arg
1 63998360 rs759233815 A G 1 0.00052 EFCAB7 missense variant p.Arg140Gln
1 64104375 rs751121095 G A 1 0.00052 PGM1 missense variant p.Ile368Val
1 65255098 chr1:65255098 A C 1 0.00052 RAVER2 missense variant p.Pro336Thr
1 65273113 chr1:65273113 G A 1 0.00052 RAVER2 missense variant p.Lys546Glu
1 65871673 chr1:65871673 A G 1 0.00056 DNAJC6 missense variant p.Gly783Asp
1 85790511 rs189798371 G A 1 0.00052 DDAH1 missense variant p.Ile218Thr
1 92442693 chr1:92442693 G A 1 0.00053 BRDT missense variant p.Lys238Glu
1 92469982 chr1:92469982 G T 1 0.00053 BRDT missense variant p.Ile800Met
1 92979452 chr1:92979452 C T 1 0.00053 EVI5 missense variant p.Ile743Val
1 100756962 chr1:100756962 C A 1 0.00053 RTCA missense variant p.Lys348Gln
1 100964750 rs754033815 C A 1 0.00052 CDC14A missense variant p.Thr563Pro
1 109395240 chr1:109395240 C T 1 0.00052 AKNAD1 missense variant p.Asp16Gly
1 109439703 rs747080388 A G 1 0.00052 GPSM2 missense variant p.Ala92Thr
1 112999589 chr1:112999589 C T 1 0.00052 CTTNBP2NL missense variant p.Ile492Thr
1 114267385 rs747112740 C T 1 0.00052 PHTF1 missense variant p.Asn207Asp
1 114483711 rs747566932 T A 1 0.00052 HIPK1 missense variant p.Ser236Cys
1 114942135 chr1:114942135 G C 1 0.00052 TRIM33 missense variant p.Asp1022His
1 115110848 rs762953689 C T 1 0.00052 BCAS2 missense variant p.Glu194Gly
1 115238109 chr1:115238109 T G 1 0.00052 AMPD1 stop gained p.Ser28*
1 115258744 rs121434596 T C 1 0.00052 NRAS missense variant p.Gly13Asp
1 115261341 chr1:115261341 C G 1 0.00052 CSDE1 missense variant p.Pro794Ala
1 115267874 rs779445127 G A 1 0.00052 CSDE1 missense variant p.Val620Ala
1 117087219 rs754340222 C G 1 0.00054 CD58 missense variant p.Ile26Met
1 120057084 rs769334806 T C 1 0.00052 HSD3B1 missense variant p.Pro315Leu
1 120496238 chr1:120496238 C G 1 0.00052 NOTCH2 missense variant p.Pro765Ala
1 120496289 chr1:120496289 G C 1 0.00052 NOTCH2 missense variant p.Gly748Arg
1 120496295 chr1:120496295 G C 1 0.00052 NOTCH2 missense variant p.Asp746His
1 150675830 rs144616489 T A 1 0.00052 HORMAD1 missense variant p.Ser330Thr
1 150675853 chr1:150675853 C T 1 0.00052 HORMAD1 missense variant p.Asn322Ser
1 150967779 chr1:150967779 A G 1 0.00052 ANXA9 missense variant p.Cys340Tyr
1 151131346 rs779652424 A G 1 0.00055 TNFAIP8L2 missense variant p.Arg58His
1 151134560 rs184513568 T C 1 0.00052 LYSMD1 missense variant p.Arg66His
1 151139661 chr1:151139661 C G 1 0.00052 SCNM1 missense variant p.Gln92His
1 151141491 chr1:151141491 C G 1 0.00052 SCNM1 missense variant p.Arg208Pro
1 151260226 rs751192864 A G 1 0.00057 ZNF687 missense variant p.Gly487Ser
1 151378048 chr1:151378048 T G 1 0.00052 POGZ missense variant p.Pro1155Thr
1 151378361 chr1:151378361 A C 1 0.00052 POGZ missense variant p.Leu1050Phe
1 151400443 chr1:151400443 T C 1 0.00052 POGZ missense variant p.Glu312Lys
1 151747257 chr1:151747257 T C 1 0.00052 TDRKH missense variant p.Ser521Asn
1 152085433 rs750586260 C T 1 0.00052 TCHH missense variant p.Tyr87Cys
1 152187890 chr1:152187890 A C 1 0.00055 HRNR missense variant p.Gly2072Val
1 152188572 rs760657166 T A 1 0.00053 HRNR missense variant p.Tyr1845Asn
1 152191367 chr1:152191367 T G 1 0.00055 HRNR missense variant p.Ser913Tyr
1 152191526 rs186602563 G C 1 0.00053 HRNR missense variant p.Ser860Thr
1 152191748 rs761620569 A C 1 0.00054 HRNR missense variant p.Gly786Val
1 152277317 chr1:152277317 A C 1 0.00053 FLG stop gained p.Glu3349*
1 152280757 chr1:152280757 G C 1 0.00052 FLG missense variant p.Gly2202Ala
1 152280764 chr1:152280764 T C 1 0.00052 FLG missense variant p.Gly2200Arg
1 152284828 rs771331527 A G 1 0.00053 FLG missense variant p.Pro845Leu
1 152323225 chr1:152323225 C T 1 0.00052 FLG2 missense variant p.His2346Arg
1 154033441 chr1:154033441 C T 1 0.00052 NUP210L missense variant p.Ile909Val
1 154305114 chr1:154305114 A G 1 0.00052 ATP8B2 missense variant p.Arg210His
1 154317926 rs752493222 T C 1 0.00052 ATP8B2 stop gained p.Arg900*
1 154403033 rs576589094 T C 1 0.00053 IL6R missense variant p.Arg137Trp
1 155014081 rs150822628 A G 1 0.00053 DCST1 missense variant p.Arg247His
1 155161981 chr1:155161981 C T 1 0.00052 MUC1 missense variant p.Lys51Arg

1 155173022 chr1:155173022 A G 1 0.00053 THBS3 stop gained p.Arg250*

1 155233065 chr1:155233065 A G 1 0.00053 CLK2 missense variant p.Leu482Phe
1 155269913 rs754454017 A T 1 0.00057 PKLR missense variant p.Ser87Cys
1 155289628 rs781599688 G A 1 0.00052 FDPS missense variant p.Lys323Arg
1 156621272 chr1:156621272 T C 1 0.00053 BCAN missense variant p.Pro363Leu
1 156639290 chr1:156639290 T C 1 0.00057 NES missense variant p.Gly1564Arg
1 156706476 chr1:156706476 G C 1 0.00052 RRNAD1 missense variant p.Asn453Lys
1 156785853 chr1:156785853 A G 1 0.00055 SH2D2A missense variant p.Thr23Ile
1 156917740 rs766160542 A T 1 0.00054 ARHGEF11 missense variant p.Glu721Val
1 158151457 rs770171229 G C 1 0.00052 CD1D missense variant p.Arg92Gly
1 158298796 chr1:158298796 A T 1 0.00052 CD1B missense variant p.Thr299Ser
1 159019289 rs747906601 G A 1 0.00052 IFI16 missense variant p.His522Arg
1 160064898 chr1:160064898 T C 1 0.00056 IGSF8 missense variant p.Arg68Lys
1 160109762 chr1:160109762 T C 1 0.00053 ATP1A2 missense variant p.Arg1008Trp
1 160249951 chr1:160249951 C T 1 0.00052 DCAF8 missense variant p.Lys80Arg
1 160607014 chr1:160607014 G C 1 0.00052 SLAMF1 missense variant p.Val128Leu
1 160806025 rs191721381 A G 1 0.00052 CD244 missense variant p.Pro290Leu
1 160811227 chr1:160811227 G C 1 0.00052 CD244 missense variant p.Arg148Thr
1 160811631 chr1:160811631 T G 1 0.00052 CD244 missense variant p.Pro41Gln
1 161007805 chr1:161007805 T G 1 0.00054 TSTD1 missense variant p.Ala72Asp
1 161007806 chr1:161007806 T C 1 0.00054 TSTD1 missense variant p.Ala72Thr
1 161042555 chr1:161042555 T C 1 0.00054 PVRL4 missense variant p.Gly477Ser
1 161042596 chr1:161042596 A G 1 0.00054 PVRL4 missense variant p.Pro463Leu
1 161089130 rs754186210 G C 1 0.00052 NIT1 missense variant p.Ser102Cys
1 161141739 rs768971975 T C 1 0.00052 B4GALT3 missense variant p.Arg350Gln
1 161199591 rs771557332 G C 1 0.00052 NR1I3 missense variant p.Ser357Thr
1 162473602 chr1:162473602 T C 1 0.00052 UHMK1 missense variant p.Ala271Val
1 167815473 rs145191438 T C 1 0.00052 ADCY10 missense variant p.Met822Ile
1 169492469 rs756397912 C T 1 0.00052 F5 missense variant p.Gln2010Arg
1 173839561 rs779871322 A G 1 0.00052 ZBTB37 missense variant p.Met66Ile
1 173916519 rs758524800 C T 1 0.00052 RC3H1 missense variant p.Ile909Val
1 173930952 chr1:173930952 G C 1 0.00052 RC3H1 missense variant p.Val705Leu
1 179347845 rs150327590 G T 1 0.00052 AXDND1 missense variant p.Leu150Val
1 182555619 chr1:182555619 C A 1 0.00052 RNASEL missense variant p.Leu108Arg
1 182616021 chr1:182616021 A G 1 0.00052 RGS8 missense variant p.Thr149Met
1 183253860 chr1:183253860 C G 1 0.00052 NMNAT2 missense variant p.Arg172Gly
1 183495785 rs374677970 C T 1 0.00052 SMG7 missense variant p.Ser123Pro
1 183536080 rs762173491 T C 1 0.00052 NCF2 missense variant p.Arg300Gln
1 185964009 rs751427036 T A 1 0.00052 HMCN1 missense variant p.Ile1190Phe
1 186024782 chr1:186024782 G A 1 0.00052 HMCN1 missense variant p.Lys2374Glu
1 186037025 chr1:186037025 A C 1 0.00052 HMCN1 missense variant p.Leu2589Ile
1 186064381 chr1:186064381 T C 1 0.00052 HMCN1 missense variant p.Pro3434Leu
1 186097361 chr1:186097361 T G 1 0.00052 HMCN1 missense variant p.Cys4281Phe
1 186113673 rs781091193 G A 1 0.00052 HMCN1 missense variant p.Lys4702Glu
1 186120434 rs774497609 G A 1 0.00052 HMCN1 missense variant p.Asp4904Gly
1 186143771 rs533893133 G A 1 0.00052 HMCN1 missense variant p.Met5314Val
1 186147655 rs144069476 A G 1 0.00052 HMCN1 missense variant p.Gly5351Arg
1 186158805 chr1:186158805 T C 1 0.00052 HMCN1 missense variant p.Thr5568Ile
1 186329113 chr1:186329113 A C 1 0.00052 TPR missense variant p.Val403Leu
1 196696064 chr1:196696064 C T 1 0.00052 CFH missense variant p.Cys744Arg
1 196715020 chr1:196715020 G T 1 0.00052 CFH stop gained p.Tyr1128*
1 198671570 chr1:198671570 T C 1 0.00052 PTPRC missense variant p.Pro165Leu
1 198678842 chr1:198678842 G A 1 0.00058 PTPRC missense variant p.Ile354Val
1 200801885 chr1:200801885 G A 1 0.00053 CAMSAP2 missense variant p.Gln291Arg
1 200946014 chr1:200946014 A G 1 0.00057 KIF21B missense variant p.Pro1445Ser
1 201012602 chr1:201012602 T G 1 0.00052 CACNA1S missense variant p.Pro1619Thr
1 201013544 rs762847052 C A 1 0.00055 CACNA1S missense variant p.Ile1570Ser
1 201020206 chr1:201020206 A G 1 0.00053 CACNA1S missense variant p.Pro1340Leu
1 201060830 rs763260505 A G 1 0.00053 CACNA1S missense variant p.Ala211Val
1 201772802 rs777253346 A G 1 0.00052 NAV1 missense variant p.Ser1200Asn
1 203143649 chr1:203143649 T G 1 0.00056 MYBPH missense variant p.Asp139Glu
1 203148927 rs765522974 T A 1 0.00053 CHI3L1 missense variant p.Trp325Arg
1 203192776 chr1:203192776 T C 1 0.00054 CHIT1 missense variant p.Met109Ile
1 203767455 chr1:203767455 C G 1 0.00052 ZBED6 missense variant p.Val269Leu
1 205589257 chr1:205589257 G A 1 0.00052 ELK4 missense variant p.Val306Ala
1 207040733 chr1:207040733 T C 1 0.00052 IL20 missense variant p.Ala128Val
1 207134442 chr1:207134442 T G 1 0.00056 FCAMR missense variant p.Thr260Lys
1 207240960 chr1:207240960 T G 1 0.00052 PFKFB2 missense variant p.Arg250Leu
1 207318001 rs770445743 C T 1 0.00052 C4BPA missense variant p.Ile578Thr

1 207498991 chr1:207498991 G A 1 0.00052 CD55 missense variant p.Glu168Gly

1 207504518 rs748840094 T G 1 0.00052 CD55 stop gained p.Gly244*
1 207642048 rs769415969 T C 1 0.00052 CR2 missense variant p.Pro208Ser
missense variant &
1 207782637 chr1:207782637 T A 1 0.00052 CR1 splice region variant p.Ile1967Leu
1 207790072 chr1:207790072 A C 1 0.00052 CR1 missense variant p.Arg2272Ser
1 207791569 chr1:207791569 A G 1 0.00052 CR1 missense variant p.Ser2348Asn
1 209783218 chr1:209783218 T G 1 0.00052 CAMK1G missense variant p.Leu257Phe
1 211545599 chr1:211545599 C T 1 0.00052 TRAF5 missense variant p.Val410Ala
1 223283834 rs778914774 C T 1 0.00052 TLR5 missense variant p.Asn847Ser
1 223285383 chr1:223285383 T C 1 0.00052 TLR5 missense variant p.Ala331Thr
1 223285788 chr1:223285788 C T 1 0.00052 TLR5 missense variant p.Lys196Glu
1 223988446 chr1:223988446 G C 1 0.00052 TP53BP2 missense variant p.Gly431Ala
1 235969755 chr1:235969755 A T 1 0.00052 LYST missense variant p.His894Leu
1 235976285 chr1:235976285 C T 1 0.00052 LYST missense variant p.Glu90Gly
1 236706938 chr1:236706938 G A 1 0.00052 LGALS8 missense variant p.Asn252Asp
1 236730038 rs369632116 T G 1 0.00052 HEATR1 missense variant p.Leu1406Met
1 247013491 chr1:247013491 A T 1 0.00052 AHCTF1 missense variant p.Arg1974Ser
1 247013587 chr1:247013587 A T 1 0.00052 AHCTF1 missense variant p.Arg1942Ser
1 247027372 rs759273373 G A 1 0.00052 AHCTF1 missense variant p.Ser1167Pro
missense variant &
1 247040602 chr1:247040602 A C 1 0.00052 AHCTF1 splice region variant p.Cys923Phe
1 247588157 chr1:247588157 G C 1 0.00052 NLRP3 missense variant p.Ser471Cys
2 11355692 rs753011445 C T 1 0.00052 ROCK2 missense variant p.Glu514Gly
2 23919236 chr2:23919236 C T 1 0.00053 KLHL29 missense variant p.Val653Ala
2 24092612 chr2:24092612 A G 1 0.00052 ATAD2B missense variant p.His333Tyr
2 24302399 chr2:24302399 T C 1 0.00052 TP53I3 missense variant p.Gly244Asp
2 24360783 chr2:24360783 G T 1 0.00054 FAM228B missense variant p.Leu58Arg
2 24522977 rs781391253 T C 1 0.00052 ITSN2 missense variant p.Arg382His
2 24930558 chr2:24930558 C A 1 0.00052 NCOA1 missense variant p.Lys740Thr
missense variant &
2 24952371 rs142674833 A G 1 0.00052 NCOA1 splice region variant p.Gly963Glu
2 25045402 chr2:25045402 C T 1 0.00052 ADCY3 missense variant p.Asn994Ser
2 25471073 chr2:25471073 C T 1 0.00055 DNMT3A missense variant p.Asn230Asp
2 26204555 rs769044393 T C 1 0.00056 KIF3C missense variant p.Val78Met
2 26607864 chr2:26607864 C T 1 0.00052 EPT1 missense variant p.Tyr257His
2 26671665 chr2:26671665 A C 1 0.00054 DRC1 missense variant p.Asp501Glu
2 27015410 chr2:27015410 G A 1 0.00053 CENPA missense variant p.Asn84Ser
2 27259596 chr2:27259596 A G 1 0.00052 TMEM214 missense variant p.Val284Met
2 27327510 chr2:27327510 G C 1 0.00055 CGREF1 missense variant p.Val31Leu
2 27351889 chr2:27351889 A G 1 0.00052 ABHD1 missense variant p.Asp118Asn
2 27500791 chr2:27500791 T G 1 0.00052 DNAJC5G missense variant p.Asp95Tyr
2 27601915 chr2:27601915 A G 1 0.00053 ZNF513 missense variant p.Ser73Phe
2 27684321 chr2:27684321 T C 1 0.00052 IFT172 missense variant p.Glu753Lys
2 27851368 rs188110444 A C 1 0.00052 CCDC121 missense variant p.Arg88Leu
2 27887385 chr2:27887385 T C 1 0.00052 SLC4A1AP stop gained p.Arg256*
2 28081344 rs147662293 T C 1 0.00052 RBKS missense variant p.Ala62Thr
2 28999758 rs760562458 A G 1 0.00052 PPP1CB missense variant p.Ala32Thr
2 29063332 chr2:29063332 C G 1 0.00052 SPDYA missense variant p.Glu283Gln
2 29222155 chr2:29222155 C G 1 0.00056 FAM179A missense variant p.Gly83Ala
missense variant &
2 30682588 chr2:30682588 C G 1 0.00052 LCLAT1 splice region variant p.Gly37Ala
2 30966265 chr2:30966265 C T 1 0.00052 CAPN13 missense variant p.Met477Val
2 31425957 chr2:31425957 A C 1 0.00052 CAPN14 missense variant p.Asp92Tyr
2 31483576 rs773880032 T G 1 0.00053 EHD3 missense variant p.Ala235Ser
2 32422820 rs755069292 A G 1 0.00052 SLC30A6 missense variant p.Arg237Gln
2 32530604 rs753860958 C T 1 0.00052 YIPF4 missense variant p.Val215Ala
2 32735666 chr2:32735666 T G 1 0.00052 BIRC6 missense variant p.Gln3437His
2 33335810 rs755344524 T C 1 0.00052 LTBP1 missense variant p.Pro342Leu
2 33498801 chr2:33498801 C T 1 0.00052 LTBP1 missense variant p.Ile900Thr
2 37310480 rs764689790 C G 1 0.00052 HEATR5B missense variant p.Ile26Met
2 39553381 chr2:39553381 T C 1 0.00052 MAP4K3 missense variant p.Gly190Ser
2 43514109 chr2:43514109 T G 1 0.00052 THADA missense variant p.Ala1701Asp
2 45807071 chr2:45807071 C G 1 0.00052 SRBD1 missense variant p.Leu339Val
2 46378210 chr2:46378210 A G 1 0.00053 PRKCE missense variant p.Val588Met
2 46602856 chr2:46602856 C G 1 0.00054 EPAS1 missense variant p.Gly305Ala
2 61275738 chr2:61275738 A T 1 0.00052 PEX13 missense variant p.Ser349Thr
2 61473490 chr2:61473490 G C 1 0.00053 USP34 missense variant p.Val2173Leu
2 68365908 chr2:68365908 T A 1 0.00052 WDR92 missense variant p.Met200Lys

2 68384615 chr2:68384615 G A 1 0.00052 RP11-474G23.1 missense variant p.Leu325Pro

2 68384796 chr2:68384796 T C 1 0.00053 RP11-474G23.1 missense variant p.Gly265Ser
2 69590685 chr2:69590685 C T 1 0.00052 GFPT1 missense variant p.Lys114Arg
2 69709811 chr2:69709811 T C 1 0.00053 AAK1 missense variant p.Met833Ile
2 69769789 chr2:69769789 A C 1 0.00052 AAK1 missense variant p.Val134Leu
2 73198715 chr2:73198715 G T 1 0.00054 SFXN5 missense variant p.Lys242Thr
2 74717515 chr2:74717515 C G 1 0.00054 TTC31 missense variant p.Ser126Thr
missense variant &
2 87015654 chr2:87015654 C G 1 0.00052 CD8A splice region variant p.Arg260Gly
2 98382607 rs751344985 T C 1 0.00052 TMEM131 missense variant p.Asp1565Asn
2 98428991 chr2:98428991 T C 1 0.00052 TMEM131 missense variant p.Gly586Arg
missense variant &
2 98431769 rs777316829 A T 1 0.00052 TMEM131 splice region variant p.His319Leu
2 100623724 rs140526847 C T 1 0.00052 AFF3 missense variant p.Ile150Val
2 102507680 chr2:102507680 T C 1 0.00052 MAP4K4 missense variant p.Thr1311Ile
2 102509737 rs146402687 A T 1 0.00052 FLJ20373 stop gained p.Leu172*
2 102954780 rs771730337 T A 1 0.00053 IL1RL1 missense variant p.Lys19Met
2 102955351 chr2:102955351 T A 1 0.00052 IL1RL1 missense variant p.Gln39Leu
2 109513434 chr2:109513434 T A 1 0.00054 EDAR missense variant p.Ser458Thr
2 128322932 chr2:128322932 C T 1 0.00056 MYO7B missense variant p.Leu86Pro
2 128339504 chr2:128339504 G C 1 0.00057 MYO7B missense variant p.His373Gln
2 128707502 chr2:128707502 T C 1 0.00052 SAP130 missense variant p.Arg939Gln
2 128712754 rs376315873 A G 1 0.00053 SAP130 missense variant p.Pro769Leu
2 133539592 rs780737770 T G 1 0.00052 NCKAP5 missense variant p.Leu1598Met
2 133539733 chr2:133539733 C T 1 0.00052 NCKAP5 missense variant p.Arg1551Gly
2 135712103 chr2:135712103 T A 1 0.00052 CCNT2 missense variant p.Glu693Val
2 135756467 rs141899370 C G 1 0.00053 MAP3K19 missense variant p.Arg139Gly
2 136362420 chr2:136362420 T G 1 0.00053 R3HDM1 missense variant p.Arg2Met
2 152132350 rs766955341 A T 1 0.00052 NMI missense variant p.Lys123Asn
2 152319950 chr2:152319950 G A 1 0.00053 RIF1 missense variant p.Met1306Val
2 152330569 chr2:152330569 C A 1 0.00053 RIF1 missense variant p.Glu2396Ala
2 160599702 chr2:160599702 G C 1 0.00052 MARCH7 missense variant p.Ser95Cys
missense variant &
2 160824050 chr2:160824050 A C 1 0.00052 PLA2R1 splice region variant p.Lys968Asn
2 163046214 chr2:163046214 C T 1 0.00053 FAP missense variant p.Ile501Val
2 163066471 chr2:163066471 G C 1 0.00052 FAP missense variant p.Trp346Cys
2 163080142 chr2:163080142 C T 1 0.00052 FAP missense variant p.Tyr130Cys
2 163163228 chr2:163163228 T C 1 0.00052 IFIH1 missense variant p.Val254Ile
2 163174615 chr2:163174615 C T 1 0.00053 IFIH1 missense variant p.Lys68Arg
2 163204145 rs751929215 G A 1 0.00052 GCA missense variant p.Thr29Ala
2 169622848 rs773417516 T C 1 0.00052 CERS6 missense variant p.Pro340Leu
2 169681188 chr2:169681188 A C 1 0.00052 NOSTRIN missense variant p.Ala53Glu
missense variant &
2 169948301 rs754460573 T C 1 0.00052 DHRS9 splice region variant p.Arg252Trp
2 170030471 rs764887934 C T 1 0.00052 LRP2 missense variant p.Asn3658Asp
2 170093681 chr2:170093681 T G 1 0.00052 LRP2 missense variant p.Ser1541Arg
2 170101218 chr2:170101218 T C 1 0.00052 LRP2 missense variant p.Asp1139Asn
2 170163901 rs759417883 A C 1 0.00052 LRP2 missense variant p.Ser106Ile
2 173352342 chr2:173352342 G T 1 0.00052 ITGA6 missense variant p.Phe782Cys
2 173429386 rs766194416 C T 1 0.00052 PDK1 missense variant p.Ile209Thr
2 179411904 rs541040798 A G 1 0.00052 TTN missense variant p.Arg31450Cys
2 179416689 chr2:179416689 T G 1 0.00052 TTN stop gained p.Ser30313*
2 179417556 chr2:179417556 A G 1 0.00052 TTN missense variant p.Pro30024Leu
2 179419339 chr2:179419339 T C 1 0.00052 TTN missense variant p.Val29579Ile
2 179436520 rs776673912 T C 1 0.00052 TTN missense variant p.Arg24780Gln
2 179439589 chr2:179439589 G A 1 0.00052 TTN missense variant p.Val23757Ala
2 179439763 chr2:179439763 T C 1 0.00052 TTN missense variant p.Ser23699Asn
2 179439827 chr2:179439827 T G 1 0.00052 TTN missense variant p.Gln23678Lys
2 179440124 chr2:179440124 C A 1 0.00052 TTN missense variant p.Trp23579Gly
2 179441911 chr2:179441911 A T 1 0.00052 TTN missense variant p.Asn23051Tyr
2 179443428 chr2:179443428 A G 1 0.00052 TTN missense variant p.Pro22747Ser
2 179452524 chr2:179452524 T G 1 0.00052 TTN missense variant p.Pro21171His
2 179463983 rs766906652 G A 1 0.00052 TTN missense variant p.Ile18846Thr
2 179477250 chr2:179477250 A C 1 0.00052 TTN missense variant p.Ala16668Ser
2 179486355 rs768414586 G C 1 0.00052 TTN missense variant p.Gly15066Arg
2 179495856 chr2:179495856 T C 1 0.00052 TTN missense variant p.Arg14640His
2 179499131 chr2:179499131 T A 1 0.00053 TTN missense variant p.Val14126Glu
2 179500824 rs727504774 T C 1 0.00052 TTN missense variant p.Arg13825Gln
2 179518183 chr2:179518183 T G 1 0.00052 TTN missense variant p.Pro12893His

2 179527104 rs779791341 T C 1 0.00055 TTN missense variant p.Val12334Met

2 179542425 rs764585210 G A 1 0.00052 TTN missense variant p.Val11405Ala
2 179579754 chr2:179579754 A T 1 0.00052 TTN missense variant p.Asp8720Val
2 179595004 chr2:179595004 T C 1 0.00052 TTN missense variant p.Met6041Ile
2 179605752 rs397517830 T C 1 0.00052 TTN missense variant p.Glu4070Lys
2 179621261 chr2:179621261 C A 1 0.00052 TTN missense variant p.Ser3648Ala
2 179640287 rs767322897 T C 1 0.00052 TTN missense variant p.Val2102Met
2 179664272 chr2:179664272 C T 1 0.00054 TTN missense variant p.Ile286Val
2 181922463 chr2:181922463 G A 1 0.00052 UBE2E3 missense variant p.Ile97Val
2 182359500 chr2:182359500 G A 1 0.00052 ITGA4 missense variant p.Ile434Val
2 183703335 rs758921569 T C 1 0.00052 FRZB missense variant p.Arg200Gln
2 183859591 chr2:183859591 A C 1 0.00052 NCKAP1 missense variant p.Asp262Tyr
2 198571321 chr2:198571321 T G 1 0.00052 MARS2 stop gained p.Glu398*
2 198948896 rs771861039 T C 1 0.00052 PLCL1 missense variant p.Arg219Trp
2 198949716 chr2:198949716 A G 1 0.00052 PLCL1 missense variant p.Gly492Glu
2 198949836 rs777477678 G A 1 0.00052 PLCL1 missense variant p.Lys532Arg
2 202093772 rs151011448 A G 1 0.00052 CASP10 missense variant p.Arg511Gln
2 203152396 chr2:203152396 G A 1 0.00052 NOP58 missense variant p.Arg150Gly
2 203420137 rs755765731 A C 1 0.00052 BMPR2 missense variant p.Asn583Lys
2 204736181 chr2:204736181 T C 1 0.00052 CTLA4 missense variant p.Leu180Phe
missense variant &
2 216229603 chr2:216229603 T C 1 0.00052 FN1 splice region variant p.Arg2417Gln
2 216256433 chr2:216256433 A G 1 0.00053 FN1 missense variant p.Arg1392Cys
2 216263988 chr2:216263988 T C 1 0.00052 FN1 missense variant p.Gly1114Ser
2 219000467 rs200906463 A G 1 0.00053 CXCR2 missense variant p.Ala315Thr
2 219855702 chr2:219855702 C G 1 0.00052 CRYBA2 missense variant p.Ser106Arg
2 228155568 chr2:228155568 A C 1 0.00052 COL4A3 stop gained p.Ser1059*
2 231042338 chr2:231042338 C A 1 0.00052 SP110 missense variant p.Phe502Leu
2 233839504 rs186848841 T C 1 0.00052 NGEF missense variant p.Glu33Lys
2 233995240 chr2:233995240 A G 1 0.00052 INPP5D missense variant p.Ala183Thr
2 234231596 chr2:234231596 G C 1 0.00052 SAG missense variant p.Pro127Arg
2 234255546 chr2:234255546 A C 1 0.00052 SAG missense variant p.Asp402Glu
2 237406115 chr2:237406115 T C 1 0.00052 IQCA1 missense variant p.Met9Ile
missense variant &
2 241556395 rs753593237 C A 1 0.00052 CAPN10 splice region variant p.Thr134Pro
missense variant &
3 419502 chr3:419502 G A 1 0.00052 CHL1 splice region variant p.Ile585Val
3 423910 chr3:423910 A G 1 0.00052 CHL1 missense variant p.Arg642Lys
3 447213 rs139892128 C G 1 0.00052 CHL1 missense variant p.Arg1165Pro
3 3095627 rs749951952 A G 1 0.00052 CNTN4 missense variant p.Ser983Asn
3 3192625 chr3:3192625 C G 1 0.00052 CRBN missense variant p.Thr418Arg
3 3192720 chr3:3192720 T C 1 0.00052 CRBN stop gained p.Trp386*
3 4110287 chr3:4110287 A C 1 0.00052 SUMF1 missense variant p.Arg386Leu
3 4355357 rs752256260 T C 1 0.00052 SETMAR missense variant p.Ser311Leu
3 4558204 rs751806213 G A 1 0.00052 ITPR1 missense variant p.His10Arg
3 4774844 chr3:4774844 A C 1 0.00052 ITPR1 missense variant p.Leu1750Ile
3 5249805 chr3:5249805 T A 1 0.00052 EDEM1 missense variant p.Ile456Phe
3 9704036 chr3:9704036 G C 1 0.00052 MTMR14 missense variant p.Pro132Ala
3 9785920 rs754915176 G A 1 0.00054 BRPF1 missense variant p.Asn883Ser
3 9868858 chr3:9868858 C T 1 0.00052 ARPC4-TTLL3 missense variant p.Val412Ala
3 10005877 chr3:10005877 G T 1 0.00052 EMC3 missense variant p.Glu221Ala
3 10312631 rs749767833 A G 1 0.00053 TATDN2 missense variant p.Val589Met
3 10319976 chr3:10319976 T G 1 0.00055 TATDN2 missense variant p.Gly659Cys
3 12544850 rs373274480 T C 1 0.00052 TSEN2 missense variant p.Thr133Met
3 15115413 rs762060370 C T 1 0.00052 ZFYVE20 missense variant p.Asp744Gly
3 17053032 chr3:17053032 G A 1 0.00052 PLCL2 missense variant p.Ile606Val
3 19974813 rs757699669 A G 1 0.00052 EFHB missense variant p.Ala233Val
3 20027113 chr3:20027113 C T 1 0.00053 PP2D1 missense variant p.Glu551Gly
3 33093405 rs76016860 C T 1 0.00052 GLB1 missense variant p.Asp343Gly
3 38134338 rs765139538 A G 1 0.00052 DLEC1 missense variant p.Asp575Asn
3 38539176 chr3:38539176 A G 1 0.00052 EXOG missense variant p.Ala74Thr
3 38545171 chr3:38545171 G A 1 0.00053 EXOG missense variant p.Asp142Gly
3 38591990 rs199473331 T C 1 0.00056 SCN5A missense variant p.Arg1958Gln
3 38592647 rs200217157 T C 1 0.00054 SCN5A missense variant p.Arg1739Gln
3 42235341 rs376442996 C T 1 0.00052 TRAK1 missense variant p.Val309Ala
3 46003729 rs746250940 G A 1 0.00052 FYCO1 missense variant p.Ile1142Thr
3 46010120 rs768271085 A G 1 0.00052 FYCO1 stop gained p.Arg236*
3 46307012 chr3:46307012 G C 1 0.00052 CCR3 missense variant p.Ile142Met
3 46620841 chr3:46620841 G A 1 0.00053 TDGF1 missense variant p.Met70Val

3 48501189 chr3:48501189 T C 1 0.00052 ATRIP missense variant p.Ser310Phe

3 49321912 chr3:49321912 T C 1 0.00052 USP4 missense variant p.Glu793Lys
3 49335323 chr3:49335323 A C 1 0.00052 USP4 missense variant p.Met557Ile
3 49456725 rs781466698 A G 1 0.00055 AMT missense variant p.Arg222Cys
3 49569281 chr3:49569281 T C 1 0.00055 DAG1 missense variant p.Thr446Ile
3 49740157 chr3:49740157 A C 1 0.00053 RNF123 missense variant p.Ala574Asp
missense variant &
3 49753009 chr3:49753009 T G 1 0.00057 RNF123 splice region variant p.Lys1004Asn
3 49830669 rs148137199 T C 1 0.00053 CDHR4 missense variant p.Val567Met
3 49833401 rs768814405 A C 1 0.00052 CDHR4 missense variant p.Val229Phe
3 50005081 rs368376344 C T 1 0.00052 RBM6 missense variant p.Tyr75His
3 50340155 chr3:50340155 C T 1 0.00056 HYAL1 missense variant p.Gln78Arg
3 50357323 chr3:50357323 A G 1 0.00056 HYAL2 missense variant p.Arg200Trp
3 50387151 chr3:50387151 A G 1 0.00053 NPRL2 missense variant p.Thr95Ile
3 50390686 chr3:50390686 A G 1 0.00053 CYB561D2 missense variant p.Met60Ile
3 50421754 chr3:50421754 C A 1 0.00052 CACNA2D2 missense variant p.Ser175Arg
3 50684588 rs749474530 T C 1 0.00054 MAPKAPK3 missense variant p.Thr317Met
3 50685473 chr3:50685473 G A 1 0.00053 MAPKAPK3 missense variant p.Gln382Arg
3 52282183 rs375720271 A G 1 0.00054 PPM1M missense variant p.Arg242Gln
3 52360860 rs201173405 G A 1 0.00054 DNAH1 missense variant p.Ile231Val
3 52721370 chr3:52721370 T C 1 0.00052 GNL3 missense variant p.Leu61Phe
3 52812385 rs771292673 T G 1 0.00052 ITIH1 missense variant p.Leu56Phe
3 52816262 chr3:52816262 A G 1 0.00052 ITIH1 missense variant p.Met303Ile
3 52833406 rs758669573 A G 1 0.00052 ITIH3 missense variant p.Val270Met
3 52860574 chr3:52860574 T A 1 0.00055 ITIH4 missense variant p.Trp205Arg
3 52876865 rs779114178 G A 1 0.00052 TMEM110-MUSTN1 missense variant p.Tyr244His
3 53217499 chr3:53217499 T C 1 0.00055 PRKCD missense variant p.Pro230Leu
missense variant &
3 53796108 chr3:53796108 G C 1 0.00053 CACNA1D splice region variant p.Asp1310Glu
3 53883794 chr3:53883794 T G 1 0.00052 IL17RB missense variant p.Met66Ile
3 56675649 rs370672814 A G 1 0.00052 FAM208A missense variant p.Arg783Cys
3 57902736 rs752100585 T C 1 0.00052 SLMAP missense variant p.Arg731Trp
3 58381436 rs755436386 G C 1 0.00052 PXK missense variant p.Gln258Glu
3 58487273 chr3:58487273 A G 1 0.00052 KCTD6 missense variant p.Val210Met
3 62189525 rs749942817 A G 1 0.00053 PTPRG missense variant p.Ala686Thr
3 62259422 rs765533974 C A 1 0.00052 PTPRG missense variant p.Lys1123Thr
3 62268508 rs778947846 G C 1 0.00052 PTPRG missense variant p.Ala1340Gly
3 69079051 rs149174901 T G 1 0.00052 TMF1 missense variant p.Leu840Ile
3 69112200 rs547884414 C T 1 0.00052 UBA3 missense variant p.Asn209Ser
3 69230392 rs367603851 A G 1 0.00052 FRMD4B missense variant p.Pro837Ser
3 69243012 chr3:69243012 C G 1 0.00052 FRMD4B missense variant p.Gln501Glu
3 69244178 chr3:69244178 G C 1 0.00052 FRMD4B missense variant p.Glu495Gln
3 69246116 rs754526422 C T 1 0.00052 FRMD4B missense variant p.Ile343Val
3 69249968 chr3:69249968 T A 1 0.00052 FRMD4B missense variant p.Ser2Thr
3 89390209 chr3:89390209 G A 1 0.00052 EPHA3 missense variant p.Met320Val
3 93596001 chr3:93596001 C T 1 0.00052 PROS1 missense variant p.Tyr560Cys
3 93615503 chr3:93615503 C G 1 0.00053 PROS1 missense variant p.Asp294Glu
3 93619659 chr3:93619659 C T 1 0.00052 PROS1 missense variant p.Lys239Arg
3 93783386 chr3:93783386 C G 1 0.00052 NSUN3 missense variant p.Val40Leu
3 97605508 chr3:97605508 A C 1 0.00052 CRYBG3 missense variant p.Gln448Lys
3 100362472 rs116356748 T C 1 0.00053 GPR128 missense variant p.Thr314Met
3 100535598 rs745848822 A G 1 0.00052 ABI3BP missense variant p.Arg1062Trp
3 100548490 chr3:100548490 T C 1 0.00052 ABI3BP missense variant p.Arg833Gln
3 119133678 rs761071117 A G 1 0.00054 ARHGAP31 missense variant p.Glu968Lys
3 119134605 chr3:119134605 T G 1 0.00052 ARHGAP31 missense variant p.Ala1277Ser
3 121980448 rs762998933 G A 1 0.00052 CASR missense variant p.Asn189Ser
3 123663804 chr3:123663804 G A 1 0.00052 CCDC14 missense variant p.Met460Thr
3 123699321 chr3:123699321 C T 1 0.00052 ROPN1 missense variant p.Gln3Arg
3 128979481 rs760414395 T C 1 0.00052 COPG1 missense variant p.Ser320Leu
3 133327754 chr3:133327754 A G 1 0.00052 TOPBP1 missense variant p.Ala1409Val
3 133335724 chr3:133335724 C T 1 0.00055 TOPBP1 missense variant p.Ile1269Val
3 133347439 chr3:133347439 T C 1 0.00052 TOPBP1 missense variant p.Ala887Thr
3 133376680 chr3:133376680 T C 1 0.00052 TOPBP1 missense variant p.Val109Ile
3 133377907 chr3:133377907 G A 1 0.00052 TOPBP1 missense variant p.Tyr58His
3 136574215 rs140162609 G A 1 0.00052 SLC35G2 missense variant p.Ile305Val
3 138116198 chr3:138116198 A G 1 0.00055 MRAS missense variant p.Ala76Thr
3 138192431 rs773319385 G A 1 0.00052 ESYT3 missense variant p.Tyr764Cys
3 138338582 chr3:138338582 T A 1 0.00052 FAIM missense variant p.Asp5Val
3 139280070 rs761470404 A T 1 0.00052 NMNAT3 missense variant p.Ile181Phe

3 147121756 chr3:147121756 T C 1 0.00052 ZIC4 missense variant p.Glu44Lys

3 147131247 chr3:147131247 T C 1 0.00054 ZIC1 missense variant p.Thr418Ile
3 148759980 chr3:148759980 C T 1 0.00052 HLTF missense variant p.Asn724Asp
3 148778593 chr3:148778593 C T 1 0.00052 HLTF missense variant p.Thr405Ala
3 148793686 chr3:148793686 C T 1 0.00052 HLTF missense variant p.Lys126Arg
3 148880486 chr3:148880486 A G 1 0.00052 HPS3 missense variant p.Ala768Thr
3 148889981 chr3:148889981 G A 1 0.00052 HPS3 missense variant p.Tyr996Cys
3 157082210 rs767375080 G C 1 0.00052 VEPH1 missense variant p.Val407Leu
missense variant &
3 157155302 rs778015862 A C 1 0.00056 PTX3 splice region variant p.Pro44His
3 160395198 rs199795781 C G 1 0.00052 ARL14 missense variant p.Asp22His
3 160395595 rs773095286 G A 1 0.00052 ARL14 missense variant p.Gln154Arg
3 172163007 chr3:172163007 C A 1 0.00052 GHSR missense variant p.Ser349Ala
3 172224304 rs758781458 T A 1 0.00052 TNFSF10 missense variant p.Phe275Tyr
3 175165038 chr3:175165038 A G 1 0.00052 NAALADL2 missense variant p.Arg371Gln
missense variant &
3 178957851 rs3914675 T C 1 0.00055 KCNMB3 splice region variant p.Arg152His
3 186272723 chr3:186272723 A C 1 0.00052 TBCCD1 missense variant p.Cys337Phe
3 186314858 chr3:186314858 A G 1 0.00053 DNAJB11 missense variant p.Asp156Asn
3 186362569 chr3:186362569 T C 1 0.00052 FETUB missense variant p.Pro152Ser
3 186457198 chr3:186457198 A G 1 0.00052 KNG1 missense variant p.Gly374Arg
3 186459931 chr3:186459931 C G 1 0.00052 KNG1 missense variant p.Gln582His
3 187088646 chr3:187088646 A G 1 0.00052 RTP4 missense variant p.Glu76Lys
3 188202428 chr3:188202428 C T 1 0.00052 LPP missense variant p.Leu81Pro
3 190366297 chr3:190366297 A G 1 0.00052 IL1RAP missense variant p.Val506Met
3 190373951 chr3:190373951 G T 1 0.00052 IL1RAP missense variant p.Leu540Trp
3 190374046 chr3:190374046 G A 1 0.00052 IL1RAP missense variant p.Arg572Gly
3 196534761 chr3:196534761 A G 1 0.00052 PAK2 missense variant p.Asp229Asn
3 196612156 chr3:196612156 G A 1 0.00052 SENP5 missense variant p.Gln35Arg
4 15060075 chr4:15060075 T G 1 0.00052 CPEB2 missense variant p.Ser831Ile
4 15443821 rs752265309 G C 1 0.00052 C1QTNF7 missense variant p.Leu97Val
4 15556750 rs376403848 T A 1 0.00052 CC2D2A missense variant p.Met848Leu
4 15688863 chr4:15688863 C T 1 0.00053 FAM200B missense variant p.Ile88Thr
4 15688937 chr4:15688937 T G 1 0.00054 FAM200B stop gained p.Glu113*
4 15688940 chr4:15688940 A C 1 0.00054 FAM200B missense variant p.Leu114Ile
4 26483291 chr4:26483291 T C 1 0.00053 CCKAR missense variant p.Ser419Asn
4 36230220 chr4:36230220 G T 1 0.00052 ARAP2 missense variant p.Lys297Gln
4 36286149 chr4:36286149 G A 1 0.00053 DTHD1 missense variant p.Ile190Val
4 36292114 chr4:36292114 C T 1 0.00052 DTHD1 missense variant p.Val251Ala
4 36292306 chr4:36292306 T G 1 0.00052 DTHD1 missense variant p.Gly315Val
4 36309888 chr4:36309888 A C 1 0.00052 DTHD1 missense variant p.Ser538Tyr
4 36310070 chr4:36310070 A G 1 0.00052 DTHD1 missense variant p.Gly599Arg
4 36318049 rs542659542 C G 1 0.00052 DTHD1 missense variant p.Val676Leu
4 37445759 rs780612415 A G 1 0.00052 KIAA1239 missense variant p.Gly717Arg
4 38799470 rs772351679 T A 1 0.00052 TLR1 missense variant p.Ile328Asn
4 40104649 rs772027051 G A 1 0.00052 N4BP2 missense variant p.Tyr395Cys
4 40154468 chr4:40154468 A G 1 0.00052 N4BP2 missense variant p.Gly1738Arg
4 54364834 chr4:54364834 T G 1 0.00052 LNX1 missense variant p.Leu318Ile
4 55141054 rs201503614 T C 1 0.00052 PDGFRA missense variant p.Pro567Leu
4 55145007 chr4:55145007 G T 1 0.00052 PDGFRA missense variant p.Ser726Arg
4 55973917 chr4:55973917 T C 1 0.00052 KDR missense variant p.Ala467Thr
4 57777652 chr4:57777652 G A 1 0.00052 REST missense variant p.Tyr283Cys
4 57797767 rs372214552 A G 1 0.00052 REST missense variant p.Glu915Lys
4 57860919 chr4:57860919 T A 1 0.00052 POLR2B missense variant p.Met155Leu
4 68379930 rs777788368 T C 1 0.00052 CENPC missense variant p.Val436Met
4 68383899 chr4:68383899 G T 1 0.00053 CENPC missense variant p.Thr269Pro
4 74306380 chr4:74306380 G C 1 0.00052 AFP stop gained p.Ser111*
4 74351688 rs758736794 C A 1 0.00052 AFM missense variant p.Tyr127Ser
4 74853246 rs781398672 C T 1 0.00052 PPBP missense variant p.Gln91Arg
4 74964321 rs201836008 G T 1 0.00052 CXCL2 missense variant p.Lys102Thr
4 76878845 rs773963650 G C 1 0.00052 SDAD1 missense variant p.Ser532Thr
4 79443912 rs752144269 C G 1 0.00052 FRAS1 missense variant p.Gln3586His
4 79461724 chr4:79461724 T A 1 0.00054 FRAS1 missense variant p.Ile3829Phe
4 80940090 chr4:80940090 G C 1 0.00052 ANTXR2 missense variant p.Val303Leu
4 95185874 chr4:95185874 G A 1 0.00052 SMARCAD1 missense variant p.Lys433Arg
4 100460497 chr4:100460497 G C 1 0.00052 C4orf17 missense variant p.Thr269Ser
4 101109090 chr4:101109090 G T 1 0.00052 DDIT4L missense variant p.His109Pro
4 103517325 chr4:103517325 T C 1 0.00052 NFKB1 missense variant p.Pro444Leu
4 103533671 chr4:103533671 T G 1 0.00052 NFKB1 missense variant p.Ala834Ser

4 109862577 chr4:109862577 G A 1 0.00052 COL25A1 missense variant p.Ile170Thr

4 110603878 chr4:110603878 T C 1 0.00052 CCDC109B stop gained p.Gln198*
4 110763628 chr4:110763628 A T 1 0.00052 RRH missense variant p.Ser242Thr
4 110902062 rs762841951 T C 1 0.00052 EGF missense variant p.Arg768Cys
4 123301319 rs375116122 T C 1 0.00052 ADAD1 missense variant p.Thr32Met
4 123542049 chr4:123542049 A G 1 0.00052 IL21 missense variant p.Arg40Cys
4 154624499 rs751213268 T A 1 0.00052 TLR2 missense variant p.His147Leu
4 154624940 rs755459719 G A 1 0.00054 TLR2 missense variant p.Asn294Ser
4 158142850 chr4:158142850 T A 1 0.00052 GRIA2 missense variant p.Glu40Asp
4 177608376 chr4:177608376 A C 1 0.00052 VEGFC missense variant p.Leu370Phe
4 185599443 chr4:185599443 T G 1 0.00053 PRIMPOL missense variant p.Arg301Leu
4 187003717 chr4:187003717 C T 1 0.00052 TLR3 missense variant p.Ser293Pro
4 187004453 chr4:187004453 T A 1 0.00052 TLR3 missense variant p.Gln538Leu
4 187070358 chr4:187070358 A G 1 0.00053 FAM149A missense variant p.Gly200Ser
4 187074872 rs140771382 A G 1 0.00056 FAM149A missense variant p.Ala345Thr
5 640631 chr5:640631 G T 1 0.00056 CEP72 missense variant p.Leu484Arg
5 7897206 chr5:7897206 A G 1 0.00052 MTRR missense variant p.Gly627Arg
5 7897207 chr5:7897207 T G 1 0.00052 MTRR missense variant p.Gly627Val
5 33453434 chr5:33453434 G A 1 0.00052 TARS missense variant p.Asn157Asp
5 34935865 chr5:34935865 G A 1 0.00052 DNAJC21 missense variant p.Tyr81Cys
5 35807015 rs555353539 C A 1 0.00052 SPEF2 missense variant p.Arg1739Ser
5 37333578 chr5:37333578 T A 1 0.00052 NUP155 missense variant p.Leu502His
missense variant &
5 37443473 chr5:37443473 G T 1 0.00052 WDR70 splice region variant p.Cys229Gly
5 38511918 chr5:38511918 A T 1 0.00052 LIFR missense variant p.Asp237Val
5 38919318 rs556983548 T C 1 0.00054 OSMR missense variant p.Thr139Met
5 39134434 chr5:39134434 C T 1 0.00052 FYB missense variant p.Thr575Ala
5 39202725 chr5:39202725 G A 1 0.00052 FYB missense variant p.Val123Ala
5 39341377 rs533953561 T C 1 0.00052 C9 missense variant p.Arg116Gln
5 40765321 chr5:40765321 C G 1 0.00054 PRKAA1 missense variant p.Gln296Glu
5 41057219 chr5:41057219 G A 1 0.00052 MROH2B missense variant p.Leu304Pro
5 41159192 rs76528010 T C 1 0.00052 C6 missense variant p.Met616Ile
5 41159339 rs80108105 G C 1 0.00052 C6 missense variant p.Gln567His
5 41186246 rs756731027 G A 1 0.00052 C6 missense variant p.Cys218Arg
5 42800968 rs770189876 A G 1 0.00052 SEPP1 missense variant p.Arg334Trp
5 52235441 rs756236797 G A 1 0.00052 ITGA1 missense variant p.Ile1034Val
5 54527256 chr5:54527256 G T 1 0.00053 CCNO missense variant p.Met334Leu
5 56177920 chr5:56177920 T C 1 0.00052 MAP3K1 stop gained p.Gln965*
5 66391496 rs370889678 T C 1 0.00052 MAST4 missense variant p.Thr305Met
5 66398343 rs760008201 A G 1 0.00052 MAST4 missense variant p.Gly166Glu
5 68555753 chr5:68555753 A G 1 0.00052 CDK7 missense variant p.Val173Ile
5 75913572 chr5:75913572 C A 1 0.00052 F2RL2 missense variant p.Ile320Met
5 76128892 chr5:76128892 G T 1 0.00052 F2RL1 missense variant p.Phe154Val
5 77396783 chr5:77396783 T C 1 0.00053 AP3B1 missense variant p.Asp822Asn
5 77458708 chr5:77458708 A G 1 0.00052 AP3B1 missense variant p.Thr433Ile
5 77536756 chr5:77536756 G A 1 0.00052 AP3B1 missense variant p.Ile70Thr
5 82786220 rs201689008 T C 1 0.00052 VCAN missense variant p.Ala125Val
5 82837383 rs771479305 C T 1 0.00052 VCAN missense variant p.Val2854Ala
5 82841445 rs773830482 C T 1 0.00052 VCAN missense variant p.Tyr3119His
5 82841454 rs770608370 A G 1 0.00052 VCAN missense variant p.Asp3122Asn
5 96232165 rs757590989 T C 1 0.00052 ERAP2 missense variant p.Pro443Leu
5 96235881 chr5:96235881 A G 1 0.00052 ERAP2 missense variant p.Met520Ile
5 108207125 chr5:108207125 G A 1 0.00052 FER missense variant p.Asn242Ser
5 108380408 chr5:108380408 T A 1 0.00052 FER missense variant p.Thr581Ser
5 110428236 chr5:110428236 A C 1 0.00052 WDR36 missense variant p.Pro84Thr
5 114952121 chr5:114952121 C T 1 0.00053 TMED7-TICAM2 missense variant p.Ile154Val
5 131676324 chr5:131676324 T C 1 0.00052 SLC22A4 missense variant p.Thr504Ile
5 131977997 chr5:131977997 C G 1 0.00052 RAD50 missense variant p.Asp1294His
5 132052578 rs759314163 A T 1 0.00052 KIF3A missense variant p.Met239Leu
5 137519998 chr5:137519998 G C 1 0.00052 KIF20A missense variant p.Arg475Gly
5 138163340 chr5:138163340 T G 1 0.00053 CTNNA1 missense variant p.Arg332Leu
5 138210173 rs371492043 G A 1 0.00052 LRRTM2 missense variant p.Met26Thr
5 139930668 chr5:139930668 G C 1 0.00052 SRA1 missense variant p.Lys159Asn
5 140035567 chr5:140035567 G C 1 0.00052 IK missense variant p.Pro264Arg
5 140038586 rs755395781 A G 1 0.00052 IK missense variant p.Arg338Gln
5 140073232 chr5:140073232 C T 1 0.00052 HARS2 missense variant p.Tyr89His
5 140797677 chr5:140797677 A T 1 0.00052 PCDHGB7 stop gained p.Leu84*
5 140798911 chr5:140798911 A C 1 0.00056 PCDHGB7 missense variant p.Asp495Glu
5 140870891 rs762200164 C T 1 0.00053 PCDHGC5 missense variant p.Ile695Thr

5 142780394 chr5:142780394 C T 1 0.00052 NR3C1 missense variant p.Lys4Arg

5 149274824 chr5:149274824 T A 1 0.00052 PDE6A missense variant p.Ser550Arg
5 149375800 chr5:149375800 T C 1 0.00055 TIGD6 missense variant p.Gly38Ser
5 149384453 rs766913056 G T 1 0.00052 HMGXB3 missense variant p.Val13Gly
5 149429906 chr5:149429906 G A 1 0.00054 HMGXB3 missense variant p.Tyr1098Cys
5 149431355 chr5:149431355 A T 1 0.00052 HMGXB3 missense variant p.Ile1160Asn
5 150406568 chr5:150406568 A C 1 0.00052 GPX3 missense variant p.Pro117Thr
5 156566152 chr5:156566152 C T 1 0.00052 MED7 missense variant p.Ile97Met
5 156589871 rs201052186 T A 1 0.00052 FAM71B missense variant p.Ser469Thr
5 156671418 rs772726821 C T 1 0.00052 ITK missense variant p.Leu460Pro
5 179201217 rs578226932 G A 1 0.00055 MAML1 missense variant p.Tyr797Cys
5 179663388 chr5:179663388 G C 1 0.00052 MAPK9 missense variant p.Arg424Pro
5 180664023 rs770353665 A G 1 0.00052 GNB2L1 missense variant p.Thr321Met
6 3012847 chr6:3012847 C T 1 0.00052 NQO2 missense variant p.Leu81Pro
6 3127508 chr6:3127508 G A 1 0.00052 BPHL missense variant p.Lys82Glu
6 15523376 rs74907982 A G 1 0.00052 DTNBP1 missense variant p.Pro297Ser
6 20546621 chr6:20546621 A G 1 0.00052 CDKAL1 missense variant p.Glu14Lys
6 21231095 chr6:21231095 C T 1 0.00053 CDKAL1 missense variant p.Leu522Pro
6 21231134 chr6:21231134 T C 1 0.00053 CDKAL1 missense variant p.Ala535Val
missense variant &
6 24559241 rs773691612 G C 1 0.00052 KIAA0319 splice region variant p.Gly912Arg
6 30514598 rs375873464 T C 1 0.00053 GNL1 missense variant p.Arg486His
missense variant &
6 30878374 rs773111203 G C 1 0.00055 GTF2H4 splice region variant p.Thr126Arg
6 30883526 chr6:30883526 G C 1 0.00052 VARS2 missense variant p.Arg160Gly
6 30885568 rs527633192 A G 1 0.00052 VARS2 missense variant p.Val354Met
6 30893952 rs761841915 A G 1 0.00054 VARS2 missense variant p.Asp1083Asn
6 31084556 chr6:31084556 A G 1 0.00053 CDSN missense variant p.Pro279Leu
6 31474073 chr6:31474073 A C 1 0.00052 MICB missense variant p.Thr160Asn
6 31603991 chr6:31603991 T A 1 0.00053 PRRC2A missense variant p.Gln1877Leu
6 31603999 rs769170351 C T 1 0.00054 PRRC2A missense variant p.Tyr1880His
6 31611688 chr6:31611688 A G 1 0.00053 BAG6 missense variant p.Leu579Phe
6 31727879 chr6:31727879 A G 1 0.00052 MSH5 missense variant p.Met583Ile
6 32065606 chr6:32065606 T C 1 0.00052 TNXB missense variant p.Gly124Arg
6 32261258 chr6:32261258 T C 1 0.00052 C6orf10 missense variant p.Val398Ile
6 32411152 chr6:32411152 G C 1 0.00052 HLA-DRA missense variant p.Phe173Leu
6 32610413 chr6:32610413 A G 1 0.00052 HLA-DQA1 missense variant p.Glu214Lys
6 32813369 chr6:32813369 A T 1 0.00052 TAP1 missense variant p.Asp805Val
6 33170472 chr6:33170472 T G 1 0.00054 SLC39A7 missense variant p.Gly312Val
6 33259953 chr6:33259953 A G 1 0.00053 RGL2 missense variant p.Pro754Ser
6 33289632 rs201782741 A G 1 0.00053 DAXX missense variant p.Pro24Leu
6 33373314 rs775737916 C A 1 0.00055 KIFC1 missense variant p.Gln481Pro
6 35391806 chr6:35391806 A C 1 0.00057 PPARD missense variant p.Pro170Thr
6 39883943 rs772980797 G A 1 0.00053 MOCS1 missense variant p.Ile151Thr
6 47251698 chr6:47251698 G A 1 0.00052 TNFRSF21 missense variant p.Trp407Arg
6 47541896 rs770123305 A G 1 0.00052 CD2AP missense variant p.Gly213Glu
6 52619853 chr6:52619853 T G 1 0.00052 GSTA2 missense variant p.Gln54Lys
6 75890736 rs758201181 C T 1 0.00052 COL12A1 missense variant p.Thr695Ala
6 76576729 rs748073974 G A 1 0.00052 MYO6 missense variant p.Ile617Met
6 76596608 chr6:76596608 C A 1 0.00052 MYO6 missense variant p.Lys852Thr
6 84368754 rs771692440 C T 1 0.00052 SNAP91 missense variant p.Ile170Met
6 91260258 rs755212534 T C 1 0.00052 MAP3K7 missense variant p.Gly293Glu
6 111912986 rs573038591 C G 1 0.00052 TRAF3IP2 missense variant p.Leu111Val
missense variant &
6 123653072 chr6:123653072 C G 1 0.00052 TRDN splice region variant p.Pro475Ala
6 123818364 chr6:123818364 G A 1 0.00053 TRDN missense variant p.Ile276Thr
6 136687472 rs751440841 A G 1 0.00052 MAP7 stop gained p.Arg350*
6 137147510 chr6:137147510 T A 1 0.00052 PEX7 missense variant p.His81Leu
6 137476140 rs141572567 A G 1 0.00052 IL22RA2 missense variant p.Ala137Val
6 137524806 chr6:137524806 G A 1 0.00052 IFNGR1 missense variant p.Leu188Pro
6 138192497 chr6:138192497 T C 1 0.00052 TNFAIP3 stop gained p.Arg45*
6 151914315 chr6:151914315 G T 1 0.00052 CCDC170 missense variant p.Met456Arg
6 154763322 rs776457984 G C 1 0.00053 CNKSR3 missense variant p.Ala107Pro
6 158323039 chr6:158323039 A T 1 0.00052 SNX9 missense variant p.Ser194Arg
6 159457400 rs754875937 T C 1 0.00053 TAGAP missense variant p.Arg552Gln
6 161135891 chr6:161135891 T G 1 0.00052 PLG stop gained p.Glu205*
6 168312072 rs747756056 T C 1 0.00052 MLLT4 missense variant p.Ser646Phe
6 168349154 chr6:168349154 A T 1 0.00052 MLLT4 missense variant p.Ile1268Asn
6 168363211 rs770828342 C G 1 0.00052 MLLT4 missense variant p.Gln1647His

6 170844456 rs576330081 A G 1 0.00052 PSMB1 missense variant p.Pro193Leu

6 170888039 chr6:170888039 G C 1 0.00052 PDCD2 missense variant p.Gly261Ala
7 1784536 chr7:1784536 A G 1 0.00058 ELFN1 missense variant p.Gly102Ser
7 2269759 rs747588764 T G 1 0.00053 MAD1L1 missense variant p.Leu4Met
7 2771015 chr7:2771015 T C 1 0.00053 GNA12 missense variant p.Asp316Asn
7 2834725 chr7:2834725 C T 1 0.00053 GNA12 missense variant p.Tyr121Cys
7 6472582 chr7:6472582 G A 1 0.00053 DAGLB missense variant p.Ile143Thr
7 6476036 chr7:6476036 T C 1 0.00052 DAGLB missense variant p.Asp126Asn
7 17373722 rs755496764 G A 1 0.00052 AHR missense variant p.Ile298Val
7 22200139 chr7:22200139 T C 1 0.00052 RAPGEF5 missense variant p.Arg355His
7 22233141 chr7:22233141 A C 1 0.00052 RAPGEF5 missense variant p.Asp47Tyr
7 22330856 rs776635634 A G 1 0.00052 RAPGEF5 missense variant p.His76Tyr
7 38468970 rs747027899 C T 1 0.00053 AMPH missense variant p.Ile214Val
7 50547491 chr7:50547491 T C 1 0.00052 DDC missense variant p.Asp339Asn
7 55240758 rs746757722 G A 1 0.00057 EGFR missense variant p.Met668Val
7 73654389 rs781896174 A G 1 0.00053 RFC2 missense variant p.Thr191Ile
7 80088004 rs761633220 G C 1 0.00052 GNAT3 missense variant p.Asp350His
7 80378261 chr7:80378261 T C 1 0.00052 SEMA3C missense variant p.Ala617Thr
7 87168613 chr7:87168613 G A 1 0.00052 ABCB1 missense variant p.Tyr790His
7 87173539 rs773899676 T G 1 0.00052 ABCB1 missense variant p.Thr706Asn
7 87196151 rs200823786 C T 1 0.00052 ABCB1 missense variant p.Ile160Met
7 91503429 rs761977328 C G 1 0.00052 MTERF missense variant p.His227Asp
7 91670175 chr7:91670175 G A 1 0.00052 AKAP9 missense variant p.Gln1639Arg
7 91715717 chr7:91715717 A G 1 0.00053 AKAP9 missense variant p.Arg3071Lys
7 91718772 chr7:91718772 T C 1 0.00052 AKAP9 missense variant p.Ala3100Val
7 91794015 chr7:91794015 G A 1 0.00056 LRRD1 missense variant p.Tyr168His
7 92163724 rs182459371 A G 1 0.00052 RBM48 missense variant p.Val153Met
7 99655414 chr7:99655414 T C 1 0.00052 ZSCAN21 missense variant p.Pro165Ser
7 99669713 chr7:99669713 A G 1 0.00052 ZNF3 stop gained p.Arg132*
missense variant &
7 99703161 rs373162905 T C 1 0.00054 AP4M1 splice region variant p.Arg317Trp
7 99717341 chr7:99717341 T G 1 0.00052 TAF6 missense variant p.Thr10Asn
7 99764673 chr7:99764673 A G 1 0.00056 GAL3ST4 missense variant p.Arg16Trp
7 99767965 rs778573008 T C 1 0.00056 GPC2 missense variant p.Ser543Asn
7 100416243 rs541670683 A G 1 0.00056 EPHB4 missense variant p.Arg441Trp
7 103113308 chr7:103113308 G A 1 0.00052 RELN missense variant p.Leu3445Pro
missense variant &
7 103197606 rs774088356 T C 1 0.00052 RELN splice region variant p.Ser1872Asn
7 103252239 chr7:103252239 A T 1 0.00052 RELN missense variant p.Asp905Val
7 107671415 chr7:107671415 A G 1 0.00052 LAMB4 stop gained p.Gln1610*
7 107706234 rs765832432 C T 1 0.00052 LAMB4 missense variant p.Ile937Val
7 107706917 rs755148173 C T 1 0.00052 LAMB4 missense variant p.Ser859Gly
7 115889084 rs142430563 T C 1 0.00052 TES missense variant p.Arg42Cys
7 116146049 rs759051961 G C 1 0.00052 CAV2 missense variant p.Leu59Val
7 116397800 chr7:116397800 G A 1 0.00052 MET missense variant p.Ile692Val
missense variant &
7 116829445 chr7:116829445 A C 1 0.00052 ST7 splice region variant p.Asp383Glu
7 123301938 chr7:123301938 A G 1 0.00052 LMOD2 missense variant p.Glu100Lys
7 123302077 chr7:123302077 A G 1 0.00052 LMOD2 missense variant p.Gly146Glu
7 123332562 chr7:123332562 G C 1 0.00054 WASL missense variant p.Asp396His
7 123594181 chr7:123594181 G A 1 0.00052 SPAM1 missense variant p.Glu186Gly
7 128483963 chr7:128483963 G T 1 0.00053 FLNC missense variant p.Asn975Lys
7 135078895 chr7:135078895 C T 1 0.00052 CNOT4 missense variant p.Thr468Ala
7 135095310 rs184784256 G A 1 0.00053 CNOT4 missense variant p.Val259Ala
7 140378974 chr7:140378974 T C 1 0.00052 ADCK2 missense variant p.Ala367Val
7 142965270 chr7:142965270 A C 1 0.00053 GSTK1 missense variant p.His264Gln
7 142988749 rs759719769 G A 1 0.00052 CASP2 missense variant p.Asp64Gly
7 143053968 chr7:143053968 G A 1 0.00052 FAM131B missense variant p.Phe253Ser
7 154739693 chr7:154739693 A G 1 0.00052 PAXIP1 stop gained p.Arg948*
7 154760232 chr7:154760232 A G 1 0.00059 PAXIP1 missense variant p.Thr560Met
8 3205621 chr8:3205621 G T 1 0.00052 CSMD1 missense variant p.Asn1124His
8 3265630 chr8:3265630 T C 1 0.00052 CSMD1 missense variant p.Arg622Gln
8 3443747 rs777685797 C T 1 0.00052 CSMD1 missense variant p.Asn379Ser
8 11679272 chr8:11679272 C T 1 0.00052 FDFT1 missense variant p.Phe132Ser
8 17794782 chr8:17794782 T C 1 0.00052 PCM1 missense variant p.Thr79Ile
8 17796371 rs781151340 A T 1 0.00052 PCM1 missense variant p.Asp155Glu
8 17830188 rs778689206 G A 1 0.00053 PCM1 missense variant p.Lys1312Arg
8 27321446 chr8:27321446 A G 1 0.00056 CHRNA2 missense variant p.His172Tyr


8 27361123 rs759198021 A G 1 0.00052 EPHX2 region variant p.Trp63*
8 32621624 chr8:32621624 C A 1 0.00052 NRG1 missense variant p.Asn616His
8 38001870 rs551783234 G A 1 0.00053 STAR missense variant p.Leu260Pro
8 38005831 chr8:38005831 T C 1 0.00053 STAR missense variant p.Glu65Lys
8 38258525 chr8:38258525 A G 1 0.00052 LETM2 missense variant p.Arg313His
missense variant &
8 42037762 rs771818476 G A 1 0.00052 PLAT splice region variant p.Ile407Thr
missense variant &
8 42178255 chr8:42178255 A G 1 0.00054 IKBKB splice region variant p.Glu507Lys
8 42188891 chr8:42188891 A G 1 0.00052 IKBKB missense variant p.Arg91His
missense variant &
8 42218813 chr8:42218813 A G 1 0.00052 POLB splice region variant p.Gly184Asp
8 48719878 chr8:48719878 C A 1 0.00052 PRKDC missense variant p.Phe3188Leu
8 48798584 rs775866201 A G 1 0.00053 PRKDC missense variant p.Thr1565Met
8 56699017 rs769149695 T C 1 0.00052 TGS1 missense variant p.Thr187Ile
8 71499372 chr8:71499372 C G 1 0.00052 TRAM1 missense variant p.Leu204Val
8 73849779 chr8:73849779 A C 1 0.00054 KCNB2 missense variant p.Pro730Gln
8 73850063 chr8:73850063 G A 1 0.00052 KCNB2 missense variant p.Lys825Glu
8 90775067 rs764903626 A G 1 0.00052 RIPK2 missense variant p.Asp62Asn
8 99217434 rs762122486 G C 1 0.00053 NIPAL2 missense variant p.Met232Ile
8 99224722 chr8:99224722 C T 1 0.00054 NIPAL2 missense variant p.Glu189Gly
8 124790298 chr8:124790298 G A 1 0.00052 FAM91A1 missense variant p.Tyr134Cys
8 124824771 chr8:124824771 G A 1 0.00053 FAM91A1 missense variant p.Ile782Val
8 131193082 chr8:131193082 A C 1 0.00052 ASAP1 missense variant p.Gly192Val
8 133823311 chr8:133823311 A G 1 0.00052 PHF20L1 missense variant p.Val290Ile
8 133848818 chr8:133848818 T C 1 0.00052 PHF20L1 missense variant p.Ser648Leu
8 133899098 rs767101433 T C 1 0.00052 TG missense variant p.Thr494Ile
missense variant &
8 134072345 chr8:134072345 T C 1 0.00053 SLA splice region variant p.Gly61Arg
8 141810650 chr8:141810650 T A 1 0.00052 PTK2 missense variant p.Leu378Gln
8 143927994 chr8:143927994 C T 1 0.00054 GML missense variant p.Met122Thr
9 5431907 chr9:5431907 A G 1 0.00052 PLGRKT missense variant p.Ala24Val
9 15474214 rs766532453 T A 1 0.00053 PSIP1 missense variant p.Ser217Arg
9 20981639 chr9:20981639 T C 1 0.00052 FOCAD missense variant p.Ser1531Phe
9 21077511 rs761313571 C T 1 0.00052 IFNB1 missense variant p.Lys120Glu
9 21481264 rs543760462 G C 1 0.00052 IFNE missense variant p.Val144Leu
9 27289724 chr9:27289724 C T 1 0.00052 EQTN missense variant p.Asn143Asp
9 27562401 chr9:27562401 C T 1 0.00052 C9orf72 missense variant p.His193Arg
9 32472997 rs139726764 A G 1 0.00053 DDX58 missense variant p.Arg664Cys
9 32480284 chr9:32480284 C G 1 0.00052 DDX58 missense variant p.Asp569Glu
9 32526076 rs147964586 A G 1 0.00052 DDX58 missense variant p.Ala30Val
9 32630108 chr9:32630108 A G 1 0.00053 TAF1L missense variant p.His1824Tyr
9 33038714 chr9:33038714 T C 1 0.00052 DNAJA1 missense variant p.Pro336Leu
9 34724712 chr9:34724712 A G 1 0.00052 FAM205A missense variant p.Pro842Leu
9 35680970 chr9:35680970 T C 1 0.00052 CA9 missense variant p.Thr443Ile
9 35680976 chr9:35680976 T G 1 0.00052 CA9 missense variant p.Gly445Val
9 35684258 chr9:35684258 C T 1 0.00052 TPM2 missense variant p.Ile253Val
9 35714056 chr9:35714056 G A 1 0.00052 TLN1 missense variant p.Leu1048Ser
9 35736056 chr9:35736056 G A 1 0.00052 CREB3 missense variant p.Asp208Gly
9 35739077 rs752951773 A G 1 0.00052 GBA2 missense variant p.Arg579Trp
9 35740046 rs78197987 T G 1 0.00052 GBA2 missense variant p.Ala459Glu
9 35752131 chr9:35752131 T G 1 0.00052 RGP1 missense variant p.Cys354Phe
9 37126730 rs778387788 G A 1 0.00052 ZCCHC7 missense variant p.Lys134Arg
9 72741182 chr9:72741182 A T 1 0.00052 MAMDC2 missense variant p.Tyr251Asn
9 72840697 chr9:72840697 C T 1 0.00054 MAMDC2 missense variant p.Ile648Thr
9 72892266 chr9:72892266 T G 1 0.00054 SMC5 missense variant p.Asp141Tyr
9 75775217 rs746085433 A C 1 0.00052 ANXA1 missense variant p.His103Gln
9 86616625 rs770552137 T C 1 0.00052 RMI1 missense variant p.Pro242Ser
9 86617677 chr9:86617677 T G 1 0.00053 RMI1 missense variant p.Met592Ile
9 99278031 chr9:99278031 C T 1 0.00052 CDC14B missense variant p.Ile458Val
9 99413985 chr9:99413985 T C 1 0.00052 AAED1 missense variant p.Val91Ile
9 100203947 rs749923554 C A 1 0.00053 TDRD7 missense variant p.Leu215Phe
9 100672673 chr9:100672673 A T 1 0.00052 C9orf156 missense variant p.His212Leu
9 100692605 rs748415690 T G 1 0.00053 HEMGN missense variant p.Gln358Lys
9 101822201 chr9:101822201 A C 1 0.00052 COL15A1 missense variant p.Pro1123Gln
9 101894898 rs776680716 T C 1 0.00052 TGFBR1 missense variant p.Arg155Cys
9 116760613 rs534863329 T C 1 0.00052 ZNF618 stop gained p.Gln138*
9 123667366 chr9:123667366 T A 1 0.00054 TRAF1 missense variant p.Ser395Thr

9 123937321 chr9:123937321 G A 1 0.00052 CNTRL missense variant p.Lys2258Arg

9 130506928 chr9:130506928 C A 1 0.00056 SH2D3C missense variant p.Val572Gly
9 131469663 rs754199667 A G 1 0.00055 PKN3 missense variant p.Val272Met
9 134501399 rs779664732 A G 1 0.00052 RAPGEF1 missense variant p.Pro539Ser
9 135201814 rs770527045 T C 1 0.00052 SETX missense variant p.Ser1724Asn
9 135275521 chr9:135275521 A G 1 0.00052 TTF1 missense variant p.Leu498Phe
9 136227153 chr9:136227153 T C 1 0.00052 SURF2 missense variant p.Thr177Ile
9 136270439 chr9:136270439 T G 1 0.00056 C9orf96 missense variant p.Arg646Leu
9 139270848 chr9:139270848 G C 1 0.00058 SNAPC4 missense variant p.Arg1457Pro
9 139324834 rs140543689 T C 1 0.00055 INPP5E missense variant p.Gly566Asp
9 139350537 chr9:139350537 T C 1 0.00054 SEC16A missense variant p.Val1878Ile
9 139371466 chr9:139371466 A G 1 0.00057 SEC16A missense variant p.Ser201Phe
10 6066275 chr10:6066275 C T 1 0.00052 IL2RA missense variant p.Glu100Gly
10 7601802 chr10:7601802 C T 1 0.00052 ITIH5 missense variant p.His681Arg
10 7618845 chr10:7618845 C T 1 0.00053 ITIH5 missense variant p.Lys517Glu
10 7759659 rs369417932 A G 1 0.00052 ITIH2 missense variant p.Glu180Lys
10 7838115 chr10:7838115 A G 1 0.00058 ATP5C1 missense variant p.Asp30Asn
10 11543198 chr10:11543198 A G 1 0.00052 USP6NL stop gained p.Arg119*
10 14862121 chr10:14862121 G T 1 0.00052 CDNF missense variant p.Lys141Thr
10 14885423 chr10:14885423 A G 1 0.00055 HSPA14 missense variant p.Cys92Tyr
10 14909263 chr10:14909263 C T 1 0.00052 HSPA14 missense variant p.Ile392Thr
10 14976478 chr10:14976478 A C 1 0.00052 DCLRE1C missense variant p.Trp193Cys
10 16932418 chr10:16932418 A G 1 0.00052 CUBN stop gained p.Gln2903*
10 17024493 rs770647065 A G 1 0.00052 CUBN missense variant p.Ser1562Phe
10 17126274 rs771444469 G A 1 0.00052 CUBN missense variant p.Ile766Thr
10 17737161 chr10:17737161 T G 1 0.00052 STAM missense variant p.Ala217Ser
10 17756642 chr10:17756642 C A 1 0.00052 STAM missense variant p.Thr496Pro
10 26518653 chr10:26518653 G A 1 0.00052 GAD2 missense variant p.Lys263Glu
10 26559597 chr10:26559597 G C 1 0.00052 GAD2 missense variant p.Thr335Arg
10 27048038 chr10:27048038 C G 1 0.00053 ABI1 missense variant p.Ser345Cys
10 28233155 chr10:28233155 C T 1 0.00052 ARMC4 missense variant p.Lys580Arg
10 33190536 rs775441007 T C 1 0.00053 ITGB1 missense variant p.Val787Ile
10 33552685 chr10:33552685 T A 1 0.00052 NRP1 missense variant p.Ser183Thr
10 35333504 chr10:35333504 C T 1 0.00053 CUL2 missense variant p.Tyr254Cys
10 49452876 rs774906204 G A 1 0.00052 FRMPD2 missense variant p.Leu109Ser
10 50085162 rs759570261 T A 1 0.00052 WDFY4 missense variant p.His2362Leu
10 60121125 chr10:60121125 A C 1 0.00052 UBE2D1 missense variant p.Pro18Thr
10 64159393 rs781556841 T A 1 0.00052 ZNF365 missense variant p.Met357Leu
10 64159409 chr10:64159409 G C 1 0.00052 ZNF365 missense variant p.Ala362Gly
10 69700756 chr10:69700756 C T 1 0.00054 HERC4 missense variant p.Lys823Arg
10 69934296 rs111965755 T C 1 0.00052 MYPN missense variant p.Pro816Leu
missense variant &
10 70960036 chr10:70960036 C G 1 0.00052 SUPV3L1 splice region variant p.Leu433Phe
10 72357879 chr10:72357879 A G 1 0.00054 PRF1 missense variant p.Thr533Ile
10 73544777 rs757570269 A G 1 0.00056 CDH23 missense variant p.Ala1883Thr
10 73553011 chr10:73553011 G A 1 0.00052 CDH23 missense variant p.Glu2114Gly
10 73569716 chr10:73569716 A C 1 0.00055 CDH23 missense variant p.Asp2959Glu
10 73580074 rs752687627 C T 1 0.00052 PSAP missense variant p.Lys312Glu
10 75276999 rs748602458 A G 1 0.00052 USP54 missense variant p.Ala1062Val
10 75279564 rs769615440 C T 1 0.00053 USP54 missense variant p.Gln890Arg
10 75289405 chr10:75289405 G A 1 0.00052 USP54 missense variant p.Leu698Pro
10 75674612 rs371319040 C T 1 0.00052 PLAU missense variant p.Met303Thr
10 75860818 chr10:75860818 G A 1 0.00052 VCL missense variant p.Gln662Arg
missense variant &
10 82040072 chr10:82040072 A C 1 0.00056 MAT1A splice region variant p.Gly136Cys
10 87407007 chr10:87407007 T G 1 0.00052 GRID1 missense variant p.Asn715Lys
10 90429671 chr10:90429671 G A 1 0.00052 LIPF missense variant p.His177Arg
10 90668464 rs756949249 G T 1 0.00052 STAMBPL1 missense variant p.Phe85Cys
10 90984962 chr10:90984962 A G 1 0.00052 LIPA missense variant p.Pro188Ser
10 91066763 rs752866846 A T 1 0.00052 IFIT2 stop gained p.Tyr350*
10 91098604 chr10:91098604 A T 1 0.00052 IFIT3 missense variant p.Asp64Glu
10 91143404 rs771089871 A G 1 0.00052 IFIT1B missense variant p.Ala112Thr
10 91196039 chr10:91196039 A C 1 0.00052 SLC16A12 missense variant p.Ala356Ser
10 95380726 rs762426409 T C 1 0.00052 PDE6C stop gained p.Arg238*
10 95418757 chr10:95418757 T G 1 0.00052 PDE6C missense variant p.Glu712Asp
10 95452470 chr10:95452470 T C 1 0.00052 FRA10AC1 missense variant p.Asp105Asn
10 97096366 chr10:97096366 C G 1 0.00054 SORBS1 missense variant p.Ala1138Gly
10 97101125 chr10:97101125 A G 1 0.00052 SORBS1 missense variant p.Pro1123Ser
10 97983740 chr10:97983740 A G 1 0.00052 BLNK stop gained p.Arg123*

10 98079071 rs762908031 T C 1 0.00052 DNTT missense variant p.Pro144Leu

10 98087323 rs763298852 C G 1 0.00052 DNTT missense variant p.Asp325His
10 99211979 chr10:99211979 G C 1 0.00052 ZDHHC16 missense variant p.Leu126Val
10 99223635 chr10:99223635 C G 1 0.00052 MMS19 missense variant p.Ala631Gly
10 99350116 rs773907690 A C 1 0.00053 C10orf62 missense variant p.His154Gln
10 100182224 rs747984964 A G 1 0.00054 HPS1 missense variant p.Arg549Cys
10 103868821 rs773634189 T G 1 0.00052 LDB1 missense variant p.Pro324Thr
10 103900485 chr10:103900485 A T 1 0.00053 PPRC1 missense variant p.Ser740Arg
10 104269039 chr10:104269039 G A 1 0.00052 SUFU missense variant p.Tyr99Cys
10 104592290 chr10:104592290 C G 1 0.00055 CYP17A1 missense variant p.His373Asp
10 105762263 rs776323344 A G 1 0.00052 SLK missense variant p.Asp443Asn
10 105763139 rs372263493 G A 1 0.00053 SLK missense variant p.Ile735Val
10 105781469 chr10:105781469 G A 1 0.00053 SLK missense variant p.Glu1180Gly
10 105807547 chr10:105807547 C A 1 0.00052 COL17A1 missense variant p.Met762Arg
10 105830213 chr10:105830213 A G 1 0.00052 COL17A1 missense variant p.Thr193Ile
10 105920820 rs759122938 C T 1 0.00052 WDR96 missense variant p.Asn1172Ser
10 105971871 chr10:105971871 A G 1 0.00052 WDR96 missense variant p.Thr210Met
10 106019354 chr10:106019354 G A 1 0.00052 GSTO1 missense variant p.Asn55Ser
10 115349477 chr10:115349477 T C 1 0.00054 NRAP missense variant p.Arg1687Gln
10 128785866 chr10:128785866 C G 1 0.00052 DOCK1 missense variant p.Trp103Cys
10 129172375 chr10:129172375 C T 1 0.00052 DOCK1 missense variant p.Phe1170Ser
11 6415551 chr11:6415551 A T 1 0.00053 SMPD1 missense variant p.Leu537His
11 6423431 rs775422772 T A 1 0.00056 APBB1 missense variant p.Asp421Glu
11 6561164 chr11:6561164 A G 1 0.00054 DNHD1 missense variant p.Arg1160Gln
11 12231089 rs777287062 T C 1 0.00052 MICAL2 missense variant p.Ser212Leu
11 12241757 rs556662753 A G 1 0.00052 MICAL2 missense variant p.Asp320Asn
11 12244252 chr11:12244252 C T 1 0.00052 MICAL2 missense variant p.Tyr471His
11 12278446 rs199868277 T C 1 0.00053 MICAL2 missense variant p.Arg1024Trp
11 16774416 chr11:16774416 A G 1 0.00052 C11orf58 missense variant p.Arg98Gln
11 17474719 rs749771128 T C 1 0.00052 ABCC8 missense variant p.Ala375Thr
11 17590736 chr11:17590736 A G 1 0.00052 OTOG missense variant p.Val572Met
11 18050716 rs772454328 A T 1 0.00052 TPH1 missense variant p.Leu221Phe
11 18108433 rs758017855 C T 1 0.00052 SAAL1 missense variant p.Glu341Gly
11 18320479 chr11:18320479 C A 1 0.00052 HPS5 missense variant p.Cys342Gly
11 18357478 chr11:18357478 G T 1 0.00052 GTF2H1 missense variant p.Leu111Arg
11 18456337 rs777146300 T C 1 0.00052 LDHC missense variant p.Arg157Cys
11 18579789 chr11:18579789 T A 1 0.00052 UEVLD missense variant p.Val234Glu
11 18591767 chr11:18591767 T C 1 0.00052 UEVLD stop gained p.Trp117*
11 18636215 chr11:18636215 C T 1 0.00052 SPTY2D1 missense variant p.Thr536Ala
11 18636536 rs555192381 T C 1 0.00057 SPTY2D1 missense variant p.Val429Ile
11 20950016 rs757768975 A G 1 0.00052 NELL1 missense variant p.Val358Ile
11 21592458 rs754480107 T C 1 0.00052 NELL1 missense variant p.Thr738Ile
11 35229669 rs773638372 G A 1 0.00052 CD44 missense variant p.Ser478Gly
11 46783596 chr11:46783596 A G 1 0.00052 CKAP5 missense variant p.Thr1392Met
11 47296560 chr11:47296560 A G 1 0.00055 MADD missense variant p.Arg170His
11 47304084 chr11:47304084 G A 1 0.00052 MADD missense variant p.Lys541Arg
11 47307987 chr11:47307987 A G 1 0.00052 MADD missense variant p.Ser852Asn
11 57427180 rs374658636 T C 1 0.00052 CLP1 missense variant p.Arg89Cys
11 57506695 chr11:57506695 G A 1 0.00052 TMX2 missense variant p.Asp236Gly
11 57513051 chr11:57513051 C T 1 0.00052 BTBD18 missense variant p.Arg232Gly
11 57518639 chr11:57518639 C T 1 0.00052 BTBD18 missense variant p.Lys8Glu
11 58377398 chr11:58377398 T A 1 0.00052 ZFP91 missense variant p.Arg156Trp
11 59344376 rs761932791 T C 1 0.00052 OSBP missense variant p.Arg728His
11 59574239 rs748789573 C T 1 0.00053 MRPL16 missense variant p.Met113Val
11 59596976 chr11:59596976 T G 1 0.00052 GIF missense variant p.Ala412Asp
11 59626719 rs568414573 G A 1 0.00052 TCN1 missense variant p.Leu193Pro
11 59633874 rs750644060 T C 1 0.00052 TCN1 missense variant p.Glu24Lys
11 60665372 rs760498240 C T 1 0.00052 PRPF19 missense variant p.Thr455Ala
11 61578485 rs763381968 A C 1 0.00052 FADS1 missense variant p.Trp249Cys
11 63953439 chr11:63953439 A T 1 0.00055 STIP1 missense variant p.Leu48Gln
11 64532977 rs747776685 T C 1 0.00059 SF1 missense variant p.Gly534Ser
missense variant &
11 64851195 rs201897046 T C 1 0.00054 CDCA5 splice region variant p.Gly16Glu
11 65422408 chr11:65422408 G A 1 0.00055 RELA missense variant p.Met366Thr
11 65486195 chr11:65486195 A G 1 0.00052 KAT5 missense variant p.Gly467Arg
11 65487283 chr11:65487283 C G 1 0.00053 RNASEH2C missense variant p.Ala234Gly
11 65487341 chr11:65487341 C T 1 0.00053 RNASEH2C missense variant p.Met215Val
11 66241449 chr11:66241449 C T 1 0.00056 PELI3 missense variant p.Leu298Pro


11 66391439 rs754368323 A G 1 0.00052 RBM14 region variant p.Trp135*
11 66391793 chr11:66391793 G A 1 0.00054 RBM14 missense variant p.Lys149Arg
11 66392401 chr11:66392401 T G 1 0.00056 RBM14 missense variant p.Ala352Ser
11 66407523 chr11:66407523 T C 1 0.00052 RBM4 missense variant p.Ala114Val
11 66453550 chr11:66453550 C A 1 0.00055 SPTBN2 missense variant p.Val2322Gly
11 67068445 chr11:67068445 A G 1 0.00057 ANKRD13D missense variant p.Cys3Tyr
11 67164829 chr11:67164829 T C 1 0.00057 RAD9A missense variant p.Thr351Ile
11 68575043 chr11:68575043 A C 1 0.00055 CPT1A missense variant p.Trp115Cys
11 68575044 chr11:68575044 A C 1 0.00055 CPT1A missense variant p.Trp115Leu
11 68660415 chr11:68660415 T A 1 0.00052 MRPL21 missense variant p.Ser166Thr
11 68665473 rs773363270 T G 1 0.00052 MRPL21 missense variant p.Pro52Thr
11 70009495 rs374970212 A G 1 0.00052 ANO1 missense variant p.Asp609Asn
11 71628685 chr11:71628685 A C 1 0.00052 RP11-849H4.2 missense variant p.Val140Phe
11 71701716 rs773012443 T C 1 0.00052 RNF121 missense variant p.Arg194Trp
11 71726456 rs752799135 C T 1 0.00056 NUMA1 missense variant p.Asp698Gly
11 76954889 chr11:76954889 C A 1 0.00052 GDPD4 missense variant p.Phe364Cys
11 77910694 chr11:77910694 C T 1 0.00052 USP35 missense variant p.Ile287Thr
11 77924720 chr11:77924720 A C 1 0.00053 USP35 missense variant p.Ala973Glu
11 77924795 chr11:77924795 A G 1 0.00053 USP35 missense variant p.Gly998Asp
11 77937852 chr11:77937852 C T 1 0.00053 GAB2 missense variant p.Asn289Ser
11 87020553 chr11:87020553 G A 1 0.00052 TMEM135 missense variant p.Ile259Val
11 89106654 rs528433051 C T 1 0.00052 NOX4 missense variant p.Thr382Ala
11 102201801 chr11:102201801 A G 1 0.00052 BIRC3 missense variant p.Ala385Thr
11 102564734 rs376387145 C T 1 0.00052 MMP27 missense variant p.Thr366Ala
11 102665941 rs186925812 A G 1 0.00052 MMP1 missense variant p.Thr288Ile
11 102824909 rs773554450 T C 1 0.00053 MMP13 missense variant p.Glu205Lys
11 108043929 rs192893789 C A 1 0.00052 NPAT missense variant p.Asn594Lys
11 108121544 rs554805703 A G 1 0.00052 ATM missense variant p.Arg451His
11 108158421 chr11:108158421 G C 1 0.00054 ATM missense variant p.Thr1363Ser
11 108235896 rs786203721 A C 1 0.00052 ATM missense variant p.Leu2980Ile
11 111896967 chr11:111896967 C G 1 0.00052 DLAT missense variant p.Ala109Pro
11 111943820 chr11:111943820 A G 1 0.00052 PIH1D2 missense variant p.Pro27Ser
11 111953260 rs779558030 A G 1 0.00053 C11orf57 missense variant p.Arg149His
11 112072779 rs181898566 A G 1 0.00052 BCO2 missense variant p.Val354Ile
11 116729339 rs767005637 A G 1 0.00052 SIK3 missense variant p.Arg941Trp
11 117969714 rs149423953 A C 1 0.00052 TMPRSS4 missense variant p.Arg20Ser
11 118128020 chr11:118128020 C T 1 0.00052 MPZL2 missense variant p.Glu198Gly
11 118521223 rs781909091 T G 1 0.00052 PHLDB1 missense variant p.Arg1282Leu
11 118850225 rs369297325 G C 1 0.00054 FOXR1 missense variant p.Ala153Gly
11 119029055 chr11:119029055 A G 1 0.00052 ABCG4 missense variant p.Ala72Thr
11 119029587 chr11:119029587 G A 1 0.00052 ABCG4 missense variant p.Tyr462Cys
11 119045226 rs199476043 A G 1 0.00053 NLRX1 missense variant p.Arg305His
11 119050411 rs777542825 T C 1 0.00053 NLRX1 stop gained p.Arg561*
11 119050440 rs746329727 A C 1 0.00053 NLRX1 missense variant p.Ser570Arg
11 119061541 chr11:119061541 A G 1 0.00056 CCDC153 stop gained p.Gln120*
11 120198193 rs768909818 C G 1 0.00052 TMEM136 missense variant p.Gly37Arg
11 134022867 rs147905924 T C 1 0.00052 NCAPD3 missense variant p.Arg1490Gln
11 134074047 chr11:134074047 C T 1 0.00052 NCAPD3 missense variant p.Tyr370Cys
11 134119074 chr11:134119074 C G 1 0.00052 THYN1 missense variant p.Pro156Arg
12 6132847 rs756064548 T A 1 0.00054 VWF missense variant p.Val1110Glu
12 6153527 rs61748477 A G 1 0.00054 VWF missense variant p.Thr791Met
12 6637443 chr12:6637443 G C 1 0.00054 NCAPD2 missense variant p.Ala1083Gly
12 6923965 chr12:6923965 G C 1 0.00053 CD4 missense variant p.Ser138Arg
12 6924149 rs140406047 A G 1 0.00053 CD4 missense variant p.Val200Met
12 6940426 chr12:6940426 T C 1 0.00053 LEPREL2 missense variant p.Ser344Phe
12 6970139 chr12:6970139 G A 1 0.00052 USP5 missense variant p.Asn456Ser
12 7077710 rs782451030 T G 1 0.00052 PHB2 stop gained p.Cys108*
12 7173211 rs781960849 G A 1 0.00052 C1S missense variant p.Ile270Val
12 7310658 rs79149590 A C 1 0.00055 CLSTN3 missense variant p.Thr963Asn
12 7894070 chr12:7894070 C T 1 0.00052 CLEC4C missense variant p.Tyr61Cys
12 8196590 chr12:8196590 C G 1 0.00052 FOXJ2 missense variant p.Arg174Pro
12 8211697 rs370515640 T C 1 0.00052 C3AR1 missense variant p.Arg362Gln
12 8759510 rs759799595 T C 1 0.00052 AICDA missense variant p.Arg36His
12 9086467 rs773756154 T C 1 0.00052 PHC1 missense variant p.Pro634Ser
12 9220787 rs770612196 T C 1 0.00052 A2M missense variant p.Cys1467Tyr
12 14769643 chr12:14769643 T C 1 0.00052 GUCY2C missense variant p.Ser965Asn
12 14849366 chr12:14849366 C A 1 0.00052 GUCY2C missense variant p.Leu6Trp
12 15654593 chr12:15654593 T A 1 0.00052 PTPRO missense variant p.Asn234Ile

12 25274804 chr12:25274804 T G 1 0.00052 CASC1 missense variant p.Phe374Leu

12 25380180 chr12:25380180 G A 1 0.00052 KRAS missense variant p.Ile93Thr
12 31231344 chr12:31231344 C A 1 0.00052 DDX11 missense variant p.Gln6Pro
12 31236916 chr12:31236916 T C 1 0.00052 DDX11 stop gained p.Arg54*
12 32480528 rs201857634 T G 1 0.00056 BICD1 missense variant p.Gly380Val
12 32955405 chr12:32955405 T C 1 0.00052 PKP2 missense variant p.Ser744Asn
12 34179426 chr12:34179426 T C 1 0.00052 ALG10 missense variant p.Ser333Phe
12 39688290 rs373406994 A C 1 0.00057 KIF21A missense variant p.Arg1655Leu
12 39760184 rs765082569 T C 1 0.00052 KIF21A missense variant p.Ala291Thr
12 40694669 chr12:40694669 C G 1 0.00052 LRRK2 missense variant p.Gly198Ala
12 40702974 rs201013695 G A 1 0.00052 LRRK2 missense variant p.Tyr1419Cys
12 40713824 rs759685441 T A 1 0.00054 LRRK2 missense variant p.His1621Leu
12 40713825 rs765275134 A C 1 0.00053 LRRK2 missense variant p.His1621Gln
12 44176243 chr12:44176243 T G 1 0.00052 IRAK4 missense variant p.Ala359Ser
12 44196238 chr12:44196238 A G 1 0.00054 TWF1 missense variant p.Pro79Ser
12 48177940 chr12:48177940 G A 1 0.00057 HDAC7 missense variant p.Cys1004Arg
12 48457588 chr12:48457588 T C 1 0.00052 SENP1 missense variant p.Gly438Arg
12 48468218 chr12:48468218 T G 1 0.00052 SENP1 missense variant p.Pro277Thr
12 49298213 chr12:49298213 A G 1 0.00052 CCDC65 missense variant p.Ala32Thr
12 49315945 chr12:49315945 C A 1 0.00052 FKBP11 missense variant p.Leu143Arg
12 49390628 rs531994480 T G 1 0.00052 DDN missense variant p.Ser677Arg
missense variant &
12 49421922 chr12:49421922 T G 1 0.00055 KMT2D splice region variant p.Asn4795Lys
12 49426595 chr12:49426595 A G 1 0.00052 KMT2D stop gained p.Gln3965*
12 49426837 chr12:49426837 T C 1 0.00056 KMT2D missense variant p.Ser3884Asn
12 49428064 chr12:49428064 C T 1 0.00053 KMT2D missense variant p.Gln3509Arg
12 49432575 chr12:49432575 A G 1 0.00055 KMT2D missense variant p.Ala2855Val
12 49447042 chr12:49447042 T A 1 0.00052 KMT2D missense variant p.Phe301Tyr
12 51092172 chr12:51092172 C T 1 0.00052 DIP2B missense variant p.Tyr704His
12 51102337 rs746963040 A G 1 0.00052 DIP2B missense variant p.Val881Met
12 51203313 chr12:51203313 T C 1 0.00052 ATF1 missense variant p.Ala90Val
12 52284856 chr12:52284856 T C 1 0.00054 ANKRD33 missense variant p.Pro376Ser
12 53647053 rs750845106 C T 1 0.00052 MFSD5 missense variant p.Phe252Ser
12 53668773 chr12:53668773 A G 1 0.00053 ESPL1 missense variant p.Gly560Glu
12 53680248 chr12:53680248 A T 1 0.00054 ESPL1 missense variant p.Leu1243Gln
12 53701436 rs767509596 T C 1 0.00055 AAAS missense variant p.Arg493His
12 54920358 rs779095429 A G 1 0.00052 NCKAP1L missense variant p.Val735Ile
12 54926017 chr12:54926017 G C 1 0.00052 NCKAP1L missense variant p.Pro949Ala
12 54966942 rs137936270 T C 1 0.00052 PDE1B missense variant p.Ser249Leu
12 56296101 chr12:56296101 A G 1 0.00056 WIBG missense variant p.Pro57Leu
12 56351432 chr12:56351432 G C 1 0.00053 PMEL missense variant p.Val219Leu
12 56363280 chr12:56363280 A G 1 0.00052 CDK2 missense variant p.Ala170Thr
12 56397574 chr12:56397574 G A 1 0.00052 SUOX missense variant p.Glu134Gly
12 56491576 chr12:56491576 C A 1 0.00052 ERBB3 missense variant p.Tyr823Ser
12 56527902 rs771895295 T G 1 0.00052 ESYT1 missense variant p.Lys504Asn
12 56743969 rs774874986 T C 1 0.00052 STAT2 missense variant p.Arg374Gln
12 57397455 rs377628250 A G 1 0.00052 ZBTB39 missense variant p.Thr416Ile
12 57605078 chr12:57605078 A C 1 0.00056 LRP1 missense variant p.Arg4346Ser
12 57843223 chr12:57843223 A T 1 0.00052 INHBC missense variant p.Asn159Lys
12 57843425 chr12:57843425 A G 1 0.00055 INHBC missense variant p.Val227Ile
12 57922958 chr12:57922958 T C 1 0.00053 MBD6 missense variant p.Pro985Ser
12 58020616 chr12:58020616 A G 1 0.00053 B4GALNT1 missense variant p.Arg505Cys
missense variant &
12 58180073 chr12:58180073 C A 1 0.00052 TSFM splice region variant p.Glu120Ala
12 66547210 rs767684716 C T 1 0.00053 TMBIM4 missense variant p.Tyr39Cys
missense variant &
12 68708729 chr12:68708729 T C 1 0.00052 MDM1 splice region variant p.Gly500Arg
12 72771892 rs752459412 T C 1 0.00055 TRHDE missense variant p.Pro391Ser
12 96360155 rs79312289 G C 1 0.00052 AMDHD1 missense variant p.Asn354Lys
12 99192750 chr12:99192750 T C 1 0.00052 ANKS1B missense variant p.Gly1077Arg
missense variant &
12 103249110 rs199475652 C A 1 0.00052 PAH splice region variant p.His170Gln
12 104046434 chr12:104046434 C T 1 0.00052 STAB2 missense variant p.Met453Thr
12 104048432 chr12:104048432 G A 1 0.00052 STAB2 missense variant p.Arg503Gly
12 104078854 rs138445835 A G 1 0.00052 STAB2 missense variant p.Ala997Thr
12 104111602 chr12:104111602 T A 1 0.00052 STAB2 missense variant p.Ile1556Phe
12 108961086 chr12:108961086 T C 1 0.00052 ISCU stop gained p.Gln154*
12 109041247 chr12:109041247 T C 1 0.00052 CORO1C missense variant p.Asp506Asn
12 109541397 chr12:109541397 C A 1 0.00052 UNG missense variant p.Lys261Thr

missense variant &

12 109945540 rs774203713 T C 1 0.00052 UBE3B splice region variant p.Thr541Ile
12 109949059 rs376213401 A G 1 0.00052 UBE3B missense variant p.Arg636Gln
12 109972537 rs370843966 A G 1 0.00057 UBE3B missense variant p.Glu1053Lys
12 111948294 chr12:111948294 C G 1 0.00052 ATXN2 missense variant p.Gln711Glu
12 111956136 rs755386197 A G 1 0.00052 ATXN2 missense variant p.Ser521Leu
12 111956139 chr12:111956139 T C 1 0.00052 ATXN2 missense variant p.Gly520Glu
12 112280935 chr12:112280935 G A 1 0.00052 MAPKAPK5 missense variant p.Tyr22Cys
12 112485570 chr12:112485570 C T 1 0.00052 NAA25 missense variant p.Ile635Met
12 122332723 rs552043284 T C 1 0.00052 PSMD9 missense variant p.Arg73Cys
12 123238315 rs780142224 G T 1 0.00052 DENR missense variant p.Leu23Val
12 123434428 chr12:123434428 C G 1 0.00054 ABCB9 missense variant p.Leu252Val
missense variant &
12 123813442 rs757344135 G A 1 0.00052 SBNO1 splice region variant p.Phe379Leu
12 129189764 rs777057937 T C 1 0.00058 TMEM132C missense variant p.Arg751Cys
12 129299323 chr12:129299323 C T 1 0.00052 SLC15A4 missense variant p.Asn280Ser
13 21370341 chr13:21370341 C T 1 0.00052 XPO4 missense variant p.Lys891Glu
missense variant &
13 24330756 chr13:24330756 G C 1 0.00056 MIPEP splice region variant p.Ala658Pro
13 25672042 chr13:25672042 C A 1 0.00053 PABPC3 missense variant p.His569Pro
13 28626774 chr13:28626774 G T 1 0.00052 FLT3 missense variant p.Arg174Ser
13 28877500 rs763158497 T C 1 0.00057 FLT1 missense variant p.Arg1274Lys
13 28895671 rs754303774 T C 1 0.00052 FLT1 missense variant p.Val1035Met
13 31231679 chr13:31231679 T G 1 0.00052 USPL1 missense variant p.Ala489Ser
13 31231818 chr13:31231818 G C 1 0.00053 USPL1 missense variant p.Ser535Cys
13 37427768 rs757281925 T C 1 0.00053 SMAD9 missense variant p.Val350Met
13 41134585 chr13:41134585 G T 1 0.00052 FOXO1 missense variant p.Tyr348Ser
13 41517106 chr13:41517106 T G 1 0.00052 ELF1 missense variant p.Thr263Asn
13 41524074 rs753000405 G C 1 0.00052 ELF1 missense variant p.Val133Leu
13 41646921 chr13:41646921 A G 1 0.00052 WBP4 missense variant p.Ala164Thr
13 48830338 chr13:48830338 C T 1 0.00052 ITM2B missense variant p.Ile91Thr
13 49086968 rs746852001 C T 1 0.00052 RCBTB2 missense variant p.His143Arg
13 50092236 chr13:50092236 T C 1 0.00052 PHF11 missense variant p.Ala136Val
13 76164099 chr13:76164099 T C 1 0.00052 UCHL3 missense variant p.Pro101Leu
13 76164252 chr13:76164252 A G 1 0.00052 UCHL3 missense variant p.Gly152Asp
13 76335124 chr13:76335124 C G 1 0.00053 LMO7 missense variant p.Gln141His
13 76397972 chr13:76397972 C G 1 0.00052 LMO7 missense variant p.Gly1023Ala
13 76407260 rs755067327 G A 1 0.00052 LMO7 missense variant p.Lys1060Arg
13 113512550 chr13:113512550 G C 1 0.00052 ATP11A missense variant p.His871Gln
13 113556677 rs542171405 C T 1 0.00052 MCF2L missense variant p.Met54Thr
missense variant &
13 114472131 chr13:114472131 G A 1 0.00052 TMEM255B splice region variant p.Met84Val
14 20876416 chr14:20876416 T C 1 0.00052 TEP1 missense variant p.Met61Ile
14 20897481 chr14:20897481 T A 1 0.00054 KLHL33 missense variant p.Cys377Ser
14 21487849 rs372825917 A G 1 0.00052 NDRG2 missense variant p.Thr222Ile
14 21511164 chr14:21511164 G A 1 0.00055 RNASE7 missense variant p.Arg5Gly
14 21511524 chr14:21511524 T C 1 0.00052 RNASE7 stop gained p.Arg125*
14 21992478 rs370096247 T C 1 0.00052 SALL2 missense variant p.Glu462Lys
14 22111727 chr14:22111727 G C 1 0.00052 TRAV1-2 missense variant p.Arg83Gly
14 22280017 chr14:22280017 G C 1 0.00052 TRAV9-1 missense variant p.Ala69Gly
14 22466287 chr14:22466287 C G 1 0.00052 TRAV17 missense variant p.Glu73Gln
14 23237365 chr14:23237365 A G 1 0.00052 OXA1L missense variant p.Gly202Arg
14 23445709 chr14:23445709 T C 1 0.00052 AJUBA missense variant p.Ala399Thr
14 23566904 chr14:23566904 A T 1 0.00052 C14orf119 missense variant p.Phe13Ile
14 23745607 rs73602454 A G 1 0.00052 HOMEZ missense variant p.Ser279Leu
14 23856759 chr14:23856759 G C 1 0.00054 MYH6 missense variant p.Gln1543His
14 23894984 chr14:23894984 G T 1 0.00052 MYH7 missense variant p.Ile736Leu
14 24571998 rs766166255 G T 1 0.00053 PCK2 missense variant p.Phe424Cys
14 24588364 rs373798935 T C 1 0.00052 DCAF11 missense variant p.Arg264Cys
14 24739230 chr14:24739230 T C 1 0.00056 RABGGTA missense variant p.Arg119His
14 24798400 rs752368778 G A 1 0.00055 ADCY4 missense variant p.Leu464Pro
14 24883816 chr14:24883816 C T 1 0.00052 NYNRIN missense variant p.Ile954Thr
14 50307541 chr14:50307541 G A 1 0.00052 NEMF missense variant p.Ile134Thr
14 50318558 chr14:50318558 C A 1 0.00052 NEMF missense variant p.Val32Gly
14 55510109 rs771813922 T C 1 0.00052 SOCS4 missense variant p.Pro117Leu
missense variant &
14 62187288 chr14:62187288 T C 1 0.00052 HIF1A splice region variant p.Ala99Val
14 64681089 rs755527635 A G 1 0.00056 SYNE2 missense variant p.Val6412Met
14 64683131 chr14:64683131 T C 1 0.00052 SYNE2 missense variant p.Thr6442Ile

14 65527962 rs369004788 G C 1 0.00052 FNTB missense variant p.Leu450Val

14 65550920 rs781393600 C T 1 0.00052 MAX missense variant p.Lys90Arg
14 67850069 chr14:67850069 G C 1 0.00052 EIF2S1 missense variant p.Ala287Gly
14 70245141 chr14:70245141 C G 1 0.00052 SLC10A1 missense variant p.Phe284Leu
14 73980809 chr14:73980809 T A 1 0.00052 HEATR4 missense variant p.Leu447Gln
14 73989345 chr14:73989345 C T 1 0.00053 HEATR4 missense variant p.His171Arg
14 77705068 chr14:77705068 G C 1 0.00052 TMEM63C missense variant p.Pro228Arg
14 94754645 rs779524045 G A 1 0.00052 SERPINA10 missense variant p.Trp364Arg
14 94756648 rs774696183 T C 1 0.00057 SERPINA10 missense variant p.Asp135Asn
14 99865078 chr14:99865078 G T 1 0.00054 SETD3 missense variant p.Lys575Gln
14 101349424 chr14:101349424 A G 1 0.00053 RTL1 missense variant p.Pro568Ser
14 102793048 chr14:102793048 A G 1 0.00052 ZNF839 missense variant p.Gly339Ser
14 102808331 chr14:102808331 A G 1 0.00054 ZNF839 missense variant p.Gly867Ser
14 103369720 rs747696299 T G 1 0.00056 TRAF3 missense variant p.Glu363Asp
14 105220205 chr14:105220205 T A 1 0.00056 SIVA1 missense variant p.Gln50Leu
14 106110159 rs370671336 A C 1 0.00057 IGHG2 missense variant p.Gln153His
15 34648801 rs762688120 T G 1 0.00052 NUTM1 missense variant p.Trp864Cys
missense variant &
15 38795473 rs780796375 T A 1 0.00052 RASGRP1 splice region variant p.Asp527Glu
15 40585156 rs868163732 T C 1 0.00053 PLCB2 missense variant p.Arg766His
15 40587181 rs759781261 T C 1 0.00052 PLCB2 stop gained p.Trp621*
15 40595526 rs780036197 T C 1 0.00052 PLCB2 missense variant p.Arg65Gln
15 40685760 rs752195768 G A 1 0.00052 KNSTRN missense variant p.Thr305Ala
15 41826966 chr15:41826966 T C 1 0.00053 RPAP1 missense variant p.Ala237Thr
15 41829299 chr15:41829299 T C 1 0.00056 RPAP1 missense variant p.Glu9Lys
15 44089095 chr15:44089095 A G 1 0.00052 RP11-296A16.1 missense variant p.Ala104Val
15 49509426 chr15:49509426 C T 1 0.00052 GALK2 missense variant p.Met61Thr
15 50884362 rs750446200 A G 1 0.00052 TRPM7 missense variant p.Pro1357Leu
15 51520033 chr15:51520033 C T 1 0.00052 CYP19A1 missense variant p.Ile132Val
15 51676027 chr15:51676027 A G 1 0.00052 GLDN missense variant p.Gly160Glu
15 51696919 chr15:51696919 T G 1 0.00052 GLDN missense variant p.Val542Leu
15 52181290 rs765884770 T G 1 0.00052 TMOD3 missense variant p.Lys148Asn
15 52258005 rs200556754 C T 1 0.00052 LEO1 missense variant p.Gln252Arg
15 55483191 rs747216897 G C 1 0.00053 RSL24D1 missense variant p.Glu84Gln
15 55647009 rs777721813 T C 1 0.00052 PIGB missense variant p.Pro451Ser
15 59139640 rs776220227 C T 1 0.00052 FAM63B missense variant p.Tyr505His
15 59445847 chr15:59445847 A C 1 0.00052 MYO1E missense variant p.Val1008Leu
15 59455396 chr15:59455396 A C 1 0.00052 MYO1E stop gained p.Glu863*
15 59455489 chr15:59455489 G C 1 0.00052 MYO1E missense variant p.Asp832His
15 59528836 chr15:59528836 C T 1 0.00052 MYO1E missense variant p.Lys123Arg
15 60648141 chr15:60648141 C T 1 0.00052 ANXA2 missense variant p.Lys187Glu
15 68445937 rs772361559 G A 1 0.00052 PIAS1 missense variant p.Met282Val
15 69076852 chr15:69076852 G T 1 0.00052 ANP32A missense variant p.Lys137Thr
15 74636307 rs773957723 A G 1 0.00053 CYP11A1 missense variant p.Arg218Cys
15 75656960 rs766243508 T C 1 0.00054 MAN2C1 missense variant p.Gly157Arg
15 75668202 rs556160377 T C 1 0.00052 SIN3A missense variant p.Arg1132Gln
15 83826130 chr15:83826130 C A 1 0.00052 HDGFRP3 missense variant p.Cys141Gly
missense variant &
16 3073477 rs369375533 G C 1 0.00056 HCFC1R1 splice region variant p.Glu50Asp
16 3076523 chr16:3076523 C T 1 0.00052 THOC6 missense variant p.Ser140Pro
16 3188362 chr16:3188362 C A 1 0.00052 ZNF213 missense variant p.Asn136Thr
16 3199011 chr16:3199011 A G 1 0.00053 CASP16 missense variant p.Gly137Arg
16 3367541 chr16:3367541 A C 1 0.00052 ZNF75A missense variant p.Pro188His
16 11137925 chr16:11137925 T A 1 0.00052 CLEC16A missense variant p.Tyr604Phe
16 11525057 chr16:11525057 A C 1 0.00052 CTD-3088G3.8 missense variant p.Asp1777Tyr
16 22128183 chr16:22128183 A C 1 0.00052 VWA3A missense variant p.Pro307Thr
16 22268697 rs750035573 A G 1 0.00052 EEF2K missense variant p.Gly298Ser
16 22269077 chr16:22269077 T A 1 0.00055 EEF2K missense variant p.Asn339Tyr
16 22360729 chr16:22360729 G A 1 0.00052 CDR2 missense variant p.Ile126Thr
16 27374667 rs372491173 T C 1 0.00057 IL4R missense variant p.Pro665Leu
16 27517389 chr16:27517389 A G 1 0.00053 GTF3C1 missense variant p.Ser534Phe
16 28842289 chr16:28842289 G C 1 0.00052 ATXN2L missense variant p.Ser406Cys
16 28890023 chr16:28890023 A G 1 0.00053 ATP2A1 missense variant p.Glu11Lys
16 28944716 rs781369027 T G 1 0.00052 CD19 missense variant p.Val241Leu
16 30122719 chr16:30122719 C T 1 0.00052 GDPD3 missense variant p.Ile233Val
16 32264862 chr16:32264862 C A 1 0.00055 TP53TG3D missense variant p.Gln63Pro
16 50745281 chr16:50745281 C G 1 0.00058 NOD2 missense variant p.Val487Leu
16 50827504 chr16:50827504 G A 1 0.00052 CYLD missense variant p.Arg800Gly
16 50830312 chr16:50830312 A G 1 0.00052 CYLD missense variant p.Asp922Asn

16 56868349 chr16:56868349 T C 1 0.00052 NUP93 stop gained p.Arg578*

16 56872886 rs190565265 A G 1 0.00052 NUP93 missense variant p.Ala681Thr
16 66420908 chr16:66420908 A G 1 0.00052 CDH5 missense variant p.Ser136Asn
16 68338035 chr16:68338035 C T 1 0.00052 SLC7A6OS missense variant p.Gln191Arg
16 68842660 chr16:68842660 A C 1 0.00052 CDH1 missense variant p.Thr199Lys
16 68857386 chr16:68857386 G A 1 0.00052 CDH1 missense variant p.Asn674Ser
16 69727203 chr16:69727203 G T 1 0.00052 NFAT5 missense variant p.Phe1159Val
16 72132587 chr16:72132587 G T 1 0.00052 DHX38 missense variant p.Ser220Arg
16 72133695 rs758566056 G A 1 0.00053 DHX38 missense variant p.Tyr342Cys
16 72144861 rs753686955 T C 1 0.00058 DHX38 missense variant p.Arg1162Cys
16 72170687 chr16:72170687 T C 1 0.00052 PMFBP1 missense variant p.Ser317Asn
16 81957177 rs781130389 A G 1 0.00053 PLCG2 missense variant p.Val799Ile
missense variant &
16 81971363 chr16:81971363 G A 1 0.00052 PLCG2 splice region variant p.Asp1018Gly
16 82033159 rs756402487 T C 1 0.00052 SDR42E1 missense variant p.Ala247Thr
16 82033534 chr16:82033534 C T 1 0.00052 SDR42E1 missense variant p.Ser122Gly
17 3629460 chr17:3629460 C G 1 0.00052 GSG2 missense variant p.Trp744Ser
17 3970509 chr17:3970509 T C 1 0.00052 ZZEF1 missense variant p.Ser1368Asn
17 4074042 rs751428903 T C 1 0.00052 ANKFY1 missense variant p.Val1127Ile
17 4621619 rs376221990 A G 1 0.00052 ARRB2 missense variant p.Val250Ile
17 4647969 rs780614708 A C 1 0.00057 ZMYND15 missense variant p.Pro578His
17 4836257 rs780652188 A G 1 0.00058 GP1BA missense variant p.Val120Ile
17 4836714 chr17:4836714 C T 1 0.00052 GP1BA missense variant p.Val272Ala
missense variant &
17 4850115 chr17:4850115 A G 1 0.00052 PFN1 splice region variant p.Pro124Ser
17 4858827 chr17:4858827 A G 1 0.00052 ENO3 missense variant p.Asp265Asn
17 4859893 rs778070292 G T 1 0.00052 ENO3 missense variant p.Trp365Gly
17 4881889 chr17:4881889 G C 1 0.00052 CAMTA2 missense variant p.Glu582Gln
missense variant &
17 4904518 rs762688180 T C 1 0.00052 KIF1C splice region variant p.Thr62Met
17 5337008 rs748497469 G C 1 0.00052 C1QBP missense variant p.Cys186Ser
17 7495195 chr17:7495195 A G 1 0.00055 FXR2 missense variant p.Leu659Phe
17 7559181 chr17:7559181 A G 1 0.00053 ATP1B2 missense variant p.Val281Met
17 7592927 rs776832907 G A 1 0.00052 WRAP53 missense variant p.Ile184Val
17 7641314 chr17:7641314 A G 1 0.00052 DNAH2 missense variant p.Ala402Thr
17 11837306 rs143624582 A G 1 0.00052 DNAH9 missense variant p.Arg4136Gln
17 19250493 chr17:19250493 G A 1 0.00052 B9D1 missense variant p.Ser141Pro
17 21216804 rs771434728 A C 1 0.00057 MAP2K3 region variant p.Cys305*
17 25973582 chr17:25973582 G A 1 0.00053 LGALS9 missense variant p.Ile213Val
17 26089860 rs759222198 A G 1 0.00055 NOS2 missense variant p.His922Tyr
17 26114833 chr17:26114833 A T 1 0.00052 NOS2 missense variant p.Lys113Ile
17 33591242 chr17:33591242 G C 1 0.00052 SLFN5 stop gained p.Tyr393*
17 34191275 chr17:34191275 G A 1 0.00052 C17orf66 missense variant p.Phe181Ser
17 34431333 chr17:34431333 G T 1 0.00052 CCL4 missense variant p.Met12Arg
17 36454466 chr17:36454466 T C 1 0.00052 MRPL45 missense variant p.Arg40Cys
17 36628240 chr17:36628240 G A 1 0.00053 ARHGAP23 missense variant p.Lys704Arg
17 37825912 rs755016927 C T 1 0.00057 PNMT missense variant p.Ile78Thr
17 37948943 chr17:37948943 C T 1 0.00052 IKZF3 missense variant p.His136Arg
17 38251356 chr17:38251356 G C 1 0.00053 NR1D1 missense variant p.Met422Ile
17 38433379 rs762490491 A C 1 0.00052 WIPF2 missense variant p.Pro409Thr
17 38787050 chr17:38787050 A G 1 0.00052 SMARCE1 stop gained p.Gln315*
17 38813616 chr17:38813616 C T 1 0.00052 KRT222 missense variant p.His216Arg
17 38816383 chr17:38816383 G A 1 0.00052 KRT222 missense variant p.Ile101Thr
17 40155571 rs782268381 G T 1 0.00053 DNAJC7 missense variant p.Thr28Pro
17 40257809 rs201235598 T C 1 0.00056 DHX58 missense variant p.Arg399Gln
17 40257975 chr17:40257975 A G 1 0.00055 DHX58 missense variant p.His344Tyr
17 40260008 chr17:40260008 G C 1 0.00055 DHX58 missense variant p.Ser266Thr
17 40270392 chr17:40270392 A T 1 0.00054 KAT2A missense variant p.Tyr368Phe
17 40271354 rs782687964 T C 1 0.00052 KAT2A missense variant p.Val328Ile
17 40376852 chr17:40376852 T C 1 0.00052 STAT5B missense variant p.Arg107His
17 40842136 rs147189145 A G 1 0.00052 CNTNAP1 missense variant p.Arg589Gln
17 41180612 rs143507179 A G 1 0.00057 RND2 missense variant p.Arg201Gln
17 41246104 chr17:41246104 A T 1 0.00052 BRCA1 missense variant p.Ile482Phe
17 43316428 chr17:43316428 C T 1 0.00052 FMNL1 missense variant p.Leu359Ser
17 45820084 chr17:45820084 C G 1 0.00057 TBX21 missense variant p.Gln200His
missense variant &
17 45820439 rs768130869 G A 1 0.00054 TBX21 splice region variant p.Asn217Asp
17 45915629 rs758226121 T G 1 0.00055 SCRN2 missense variant p.Pro376Thr

17 45916930 rs773195495 A C 1 0.00055 SCRN2 missense variant p.Gly154Cys

17 47018301 chr17:47018301 T C 1 0.00052 SNF8 missense variant p.Val77Met
17 48245089 chr17:48245089 T G 1 0.00054 SGCA missense variant p.Val102Phe
17 48940763 chr17:48940763 A G 1 0.00052 TOB1 missense variant p.Pro206Ser
missense variant &
17 49156947 chr17:49156947 C T 1 0.00052 SPAG9 splice region variant p.Gln141Arg
17 54912595 chr17:54912595 A T 1 0.00052 DGKE missense variant p.Cys147Ser
17 54978936 chr17:54978936 T C 1 0.00053 TRIM25 missense variant p.Ala311Thr
17 55058579 chr17:55058579 T C 1 0.00052 SCPEP1 missense variant p.His60Tyr
17 56058153 chr17:56058153 C T 1 0.00052 VEZF1 missense variant p.Met81Val
17 56232756 chr17:56232756 A T 1 0.00052 OR4D1 missense variant p.Met81Lys
17 56434758 chr17:56434758 A C 1 0.00053 RNF43 missense variant p.Lys666Asn
17 58040502 chr17:58040502 G A 1 0.00052 RNFT1 missense variant p.Leu67Ser
17 61829344 chr17:61829344 A G 1 0.00052 RP11-51F16.8 stop gained p.Arg38*
17 61895253 chr17:61895253 T A 1 0.00053 DDX42 missense variant p.Asn771Ile
17 61895456 rs556300636 T C 1 0.00055 DDX42 missense variant p.Arg839Cys
17 61908463 rs534233529 T C 1 0.00052 PSMC5 stop gained p.Arg109*
17 64876683 rs138881080 A G 1 0.00052 CACNG5 missense variant p.Arg98His
17 72540951 rs759032539 G T 1 0.00052 CD300C missense variant p.Asp66Ala
missense variant &
17 73231295 rs768393987 G A 1 0.00052 NUP85 splice region variant p.Gln623Arg
17 73234695 chr17:73234695 A G 1 0.00054 GGA3 missense variant p.Pro74Leu
17 73258891 chr17:73258891 A C 1 0.00052 MRPS7 missense variant p.Phe123Leu
17 73727019 rs778104417 A G 1 0.00053 ITGB4 missense variant p.Val356Met
missense variant &
17 73727044 rs370095218 G A 1 0.00054 ITGB4 splice region variant p.Asn364Ser
17 74622810 rs138031739 T C 1 0.00053 ST6GALNAC1 missense variant p.Gly412Ser
17 76421538 chr17:76421538 T C 1 0.00053 DNAH17 missense variant p.Glu4367Lys
17 76831448 rs148192093 C G 1 0.00053 USP36 missense variant p.Thr130Ser
17 76968019 chr17:76968019 C T 1 0.00052 LGALS3BP missense variant p.His466Arg
17 76993315 chr17:76993315 C T 1 0.00053 CANT1 missense variant p.Lys77Glu
18 670767 rs373096647 T A 1 0.00052 TYMS missense variant p.Gln211Leu
18 743022 chr18:743022 G T 1 0.00052 YES1 missense variant p.Gln324Pro
18 2891408 chr18:2891408 A G 1 0.00052 EMILIN2 missense variant p.Gly428Glu
18 2891449 chr18:2891449 A C 1 0.00052 EMILIN2 missense variant p.Pro442Thr
18 8406128 chr18:8406128 A G 1 0.00052 PTPRM missense variant p.Glu1457Lys
18 9256796 chr18:9256796 T G 1 0.00052 ANKRD12 missense variant p.Lys1177Asn
18 12686304 rs762367925 C T 1 0.00052 CEP76 missense variant p.Gln360Arg
18 13885084 chr18:13885084 T C 1 0.00054 MC2R missense variant p.Arg145His
18 18559886 rs775538267 C T 1 0.00053 ROCK1 missense variant p.Glu880Gly
18 48581159 chr18:48581159 G A 1 0.00052 SMAD4 missense variant p.Ser155Gly
18 54362397 chr18:54362397 G A 1 0.00052 WDR7 missense variant p.Gln442Arg
18 55335743 chr18:55335743 G C 1 0.00052 ATP8B1 missense variant p.Lys709Asn
19 3735930 rs565934761 A G 1 0.00052 TJP3 missense variant p.Arg408His
19 4212678 rs375444482 T C 1 0.00056 ANKRD24 missense variant p.Arg484Trp
19 6380353 chr19:6380353 A T 1 0.00052 GTF2F1 missense variant p.Lys498Met
19 6467946 chr19:6467946 C T 1 0.00053 DENND1C missense variant p.Thr659Ala
19 6468372 chr19:6468372 C T 1 0.00056 DENND1C missense variant p.Glu555Gly
19 6697719 rs771305132 T C 1 0.00053 C3 missense variant p.Glu843Lys
19 6719341 rs780548430 C G 1 0.00057 C3 missense variant p.Gln50Glu
missense variant &
19 6735921 chr19:6735921 G A 1 0.00052 GPR108 splice region variant p.Ser97Pro
19 6832126 rs144739934 A G 1 0.00052 VAV1 missense variant p.Glu475Lys
19 7686101 rs777686042 T C 1 0.00056 XAB2 missense variant p.Arg567His
19 7689210 rs763248298 A G 1 0.00059 XAB2 missense variant p.Ser315Leu
19 7695745 chr19:7695745 G T 1 0.00053 PET100 missense variant p.Phe51Val
19 7712634 chr19:7712634 G A 1 0.00056 STXBP2 missense variant p.Thr585Ala
19 7743449 rs757755213 C T 1 0.00052 C19orf59 missense variant p.Met149Thr
19 7810715 rs745378205 G A 1 0.00054 CD209 missense variant p.Ile146Thr
19 10091356 rs368541624 A G 1 0.00053 COL5A3 stop gained p.Gln858*
19 10257109 rs770079133 C G 1 0.00053 DNMT1 missense variant p.Leu938Val
19 10395926 chr19:10395926 T C 1 0.00053 ICAM1 missense variant p.Thr521Ile
19 10812642 chr19:10812642 G A 1 0.00054 QTRT1 missense variant p.Gln87Arg
19 11033825 rs750963587 A G 1 0.00055 YIPF2 missense variant p.Ser188Phe
19 11118683 chr19:11118683 A G 1 0.00053 SMARCA4 missense variant p.Ala703Thr
19 11332620 chr19:11332620 T C 1 0.00056 DOCK6 missense variant p.Ala1153Thr
19 12126310 chr19:12126310 T G 1 0.00052 ZNF433 missense variant p.Pro458Thr
19 12841792 chr19:12841792 A G 1 0.00053 C19orf43 missense variant p.Arg172Trp
19 12858827 rs774637174 T C 1 0.00054 ASNA1 missense variant p.Pro319Leu

19 12981975 chr19:12981975 T G 1 0.00055 MAST1 missense variant p.Glu1084Asp

19 14200056 rs563414303 G C 1 0.00053 SAMD1 missense variant p.Gly252Ala
19 16268042 rs75384630 A G 1 0.00054 HSH2D missense variant p.Cys166Tyr
19 17394286 chr19:17394286 T C 1 0.00056 ANKLE1 missense variant p.Pro238Leu
19 17892605 chr19:17892605 T C 1 0.00056 FCHO1 missense variant p.Ala645Val
19 18218419 chr19:18218419 A G 1 0.00055 MAST3 missense variant p.Arg21Gln
19 18256001 rs761394244 A G 1 0.00056 MAST3 missense variant p.Gly972Ser
19 18474257 rs771517091 G C 1 0.00053 PGPEP1 missense variant p.Ala165Gly
19 18965798 chr19:18965798 C T 1 0.00057 UPF1 missense variant p.Leu470Pro
19 35775938 rs767080313 G A 1 0.00052 HAMP missense variant p.Lys83Arg
19 35802832 chr19:35802832 G C 1 0.00055 MAG missense variant p.Thr543Arg
19 35832254 chr19:35832254 G C 1 0.00055 CD22 missense variant p.Arg506Gly
19 36302916 chr19:36302916 A G 1 0.00057 PRODH2 missense variant p.Ala258Val
19 36332658 chr19:36332658 T G 1 0.00052 NPHS1 missense variant p.Ala925Asp
19 38980762 rs775643457 A G 1 0.00055 RYR1 missense variant p.Arg1954His
19 39001174 rs768538971 T C 1 0.00052 RYR1 missense variant p.Pro2990Leu
19 39307959 rs757032356 T C 1 0.00057 ECH1 missense variant p.Gly174Arg
19 39439250 rs763629297 T C 1 0.00054 CTC-360G5.8 missense variant p.Val44Met
19 39884243 rs771903804 G T 1 0.00052 MED29 missense variant p.Phe130Cys
19 39975837 chr19:39975837 G C 1 0.00054 TIMM50 missense variant p.Ser110Trp
19 39977097 rs766277051 T C 1 0.00053 TIMM50 missense variant p.Arg323Trp
19 40097959 rs193269928 C T 1 0.00052 LGALS13 missense variant p.Ser134Pro
19 41826311 chr19:41826311 A G 1 0.00055 CCDC97 missense variant p.Glu283Lys
19 42584038 chr19:42584038 T C 1 0.00058 ZNF574 missense variant p.Pro517Leu
19 49207142 chr19:49207142 A C 1 0.00052 FUT2 missense variant p.Thr310Asn
19 49376671 chr19:49376671 C G 1 0.00054 PPP1R15A missense variant p.Glu61Gln
19 49477932 chr19:49477932 T A 1 0.00054 GYS1 missense variant p.Ile456Asn
19 49930177 chr19:49930177 A G 1 0.00052 GFY missense variant p.Glu164Lys
19 49989350 chr19:49989350 A G 1 0.00052 FLT3LG missense variant p.Gly151Asp
19 50004387 chr19:50004387 A G 1 0.00059 hsa-mir-150 missense variant p.Gly203Arg
19 50138844 chr19:50138844 G C 1 0.00056 RRAS missense variant p.Val216Leu
19 50165277 rs368333462 T C 1 0.00056 IRF3 missense variant p.Gly304Arg
19 50170397 rs751409023 T C 1 0.00052 BCL2L12 missense variant p.Pro161Ser
19 50804997 rs777220522 A G 1 0.00056 MYH14 missense variant p.Arg1850Gln
19 50940957 rs750573077 C G 1 0.00052 MYBPC2 missense variant p.Ser185Thr
19 53208747 chr19:53208747 A G 1 0.00052 ZNF611 missense variant p.Arg521Cys
19 54299219 rs770386298 T G 1 0.00052 NLRP12 missense variant p.Gln999Lys
19 54848366 chr19:54848366 C A 1 0.00058 LILRA4 missense variant p.Val334Gly
19 55019328 chr19:55019328 C T 1 0.00052 LAIR2 missense variant p.Leu98Pro
19 55420766 rs759022000 T C 1 0.00054 NCR1 missense variant p.Ala173Val
19 55493915 chr19:55493915 G C 1 0.00054 NLRP2 missense variant p.Ile283Met
19 55501899 chr19:55501899 C A 1 0.00052 NLRP2 missense variant p.Asn856Thr
19 56189019 rs762919490 G C 1 0.00052 EPN1 missense variant p.Leu51Val
19 56249609 rs370177421 G C 1 0.00052 NLRP9 missense variant p.Trp44Cys
19 56369414 chr19:56369414 G A 1 0.00052 NLRP4 missense variant p.Ile219Val
19 56549541 chr19:56549541 C G 1 0.00052 NLRP5 missense variant p.Gln922His
20 1209111 chr20:1209111 G A 1 0.00052 RAD21L1 missense variant p.His5Arg
20 2636276 chr20:2636276 A G 1 0.00052 NOP56 missense variant p.Glu265Lys
20 2637178 rs758338406 T G 1 0.00053 NOP56 missense variant p.Arg381Leu
20 5924282 rs762857318 G A 1 0.00052 TRMT6 missense variant p.Ile197Thr
20 5996127 chr20:5996127 A C 1 0.00052 CRLS1 missense variant p.Leu189Ile
20 18474669 chr20:18474669 C T 1 0.00052 RBBP9 missense variant p.Thr61Ala
20 35128750 chr20:35128750 T C 1 0.00056 DLGAP4 missense variant p.Arg750Trp
20 36999931 chr20:36999931 A G 1 0.00052 LBP missense variant p.Val409Met
20 39796502 chr20:39796502 G A 1 0.00052 PLCG1 missense variant p.Tyr771Cys
20 39833241 chr20:39833241 G C 1 0.00052 ZHX3 missense variant p.Asp106His
20 43043264 chr20:43043264 C T 1 0.00055 HNF4A missense variant p.Tyr204His
20 44334528 rs770731996 C T 1 0.00052 WFDC13 missense variant p.Ile89Thr
20 44521413 rs752113422 T C 1 0.00052 CTSA missense variant p.Pro183Leu
20 44523364 chr20:44523364 T G 1 0.00053 CTSA missense variant p.Val303Leu
20 44523736 chr20:44523736 G A 1 0.00056 CTSA missense variant p.Asn369Ser
20 44527063 rs147472210 T C 1 0.00055 CTSA missense variant p.Arg491Cys
20 44533657 chr20:44533657 A G 1 0.00055 PLTP missense variant p.Ser289Phe
20 44538288 chr20:44538288 T C 1 0.00053 PLTP missense variant p.Ala138Thr
20 44669120 chr20:44669120 T A 1 0.00052 SLC12A5 missense variant p.Met264Leu
20 44698964 chr20:44698964 G C 1 0.00052 NCOA5 missense variant p.Val84Leu
20 44698973 rs746747724 T C 1 0.00052 NCOA5 missense variant p.Val81Ile
20 46276064 rs370656650 G C 1 0.00052 NCOA3 missense variant p.Pro1167Arg
20 46277774 chr20:46277774 C T 1 0.00052 NCOA3 missense variant p.Leu1191Pro

20 47628572 rs767937591 T C 1 0.00052 ARFGEF2 missense variant p.Ala1290Val

20 47691971 rs754442648 A G 1 0.00052 CSE1L missense variant p.Ala417Thr
20 47736550 chr20:47736550 A G 1 0.00052 STAU1 missense variant p.Pro361Leu
20 48524826 chr20:48524826 T C 1 0.00055 SPATA2 missense variant p.Glu68Lys
missense variant &
20 49211907 rs768291837 G C 1 0.00052 FAM65C splice region variant p.Glu683Asp
20 49236613 chr20:49236613 G A 1 0.00052 FAM65C missense variant p.Met60Thr
20 50400814 rs373555761 A G 1 0.00052 SALL4 missense variant p.Ala1051Val
20 61488954 rs528649129 A C 1 0.00053 TCFL5 missense variant p.Arg344Leu
20 61538566 rs758731690 C T 1 0.00052 DIDO1 missense variant p.Lys436Arg
20 61542285 rs768637738 A G 1 0.00053 DIDO1 missense variant p.Ser227Phe
missense variant &
20 62224435 rs776946146 G A 1 0.00052 GMEB2 splice region variant p.Val207Ala
21 26961170 chr21:26961170 T G 1 0.00052 MRPL39 missense variant p.Leu316Ile
21 26976136 chr21:26976136 C T 1 0.00053 MRPL39 missense variant p.Lys131Arg
21 33043893 chr21:33043893 G C 1 0.00052 SCAF4 missense variant p.Gly1088Ala
21 33063237 rs775209963 A C 1 0.00052 SCAF4 missense variant p.Lys586Asn
21 33065690 rs753270057 T C 1 0.00052 SCAF4 missense variant p.Arg477Gln
21 33692919 chr21:33692919 A G 1 0.00052 URB1 missense variant p.Ala1839Val
21 33711108 chr21:33711108 A G 1 0.00052 URB1 missense variant p.Pro1473Leu
21 33757904 rs114003733 C A 1 0.00052 URB1 missense variant p.Cys78Gly
21 34029111 chr21:34029111 T C 1 0.00052 SYNJ1 missense variant p.Gly933Asp
21 34115608 chr21:34115608 C T 1 0.00053 PAXBP1 missense variant p.Asn762Ser
21 34793899 rs756119057 G A 1 0.00052 IFNGR2 missense variant p.Met126Val
21 34883568 chr21:34883568 A G 1 0.00052 GART stop gained p.Arg769*
21 34951771 chr21:34951771 T G 1 0.00052 DONSON stop gained p.Ser483*
21 35140120 chr21:35140120 G A 1 0.00052 ITSN1 missense variant p.Lys344Glu
21 35147336 chr21:35147336 C G 1 0.00052 ITSN1 missense variant p.Arg507Thr
21 40552306 rs751396324 C T 1 0.00052 PSMG1 missense variant p.Lys100Glu
21 40670370 chr21:40670370 A G 1 0.00052 BRWD1 missense variant p.Arg113Cys
21 40795356 rs753208196 A T 1 0.00054 LCA5L missense variant p.Gln128Leu
21 42749774 chr21:42749774 G T 1 0.00058 MX2 missense variant p.Leu103Arg
21 42754475 rs764566059 A G 1 0.00055 MX2 missense variant p.Arg239Gln
21 42809035 rs749472574 C T 1 0.00052 MX1 missense variant p.Ile131Thr
21 43770070 chr21:43770070 G T 1 0.00056 TFF2 missense variant p.Asp50Ala
21 43838576 chr21:43838576 C T 1 0.00052 UBASH3A missense variant p.Tyr302His
21 43905847 rs778786028 T G 1 0.00052 RSPH1 missense variant p.Gln145Lys
21 45103166 rs755653178 A G 1 0.00052 RRP1B missense variant p.Gly268Asp
21 45479062 chr21:45479062 G T 1 0.00052 TRAPPC10 missense variant p.Phe253Val
21 45507594 chr21:45507594 T G 1 0.00053 TRAPPC10 missense variant p.Ala852Ser
21 45655275 rs569961030 C T 1 0.00055 ICOSLG missense variant p.Met193Val
21 46226843 rs368636514 A G 1 0.00055 SUMO3 missense variant p.Arg129Cys
22 18138586 rs773884030 C T 1 0.00052 BCL2L13 missense variant p.Ser37Pro
22 19506390 rs778665661 T C 1 0.00053 CDC45 missense variant p.Arg586Trp
22 19707965 chr22:19707965 G C 1 0.00058 SEPT5 missense variant p.Pro171Arg
22 20457733 chr22:20457733 T C 1 0.00052 RIMBP3 missense variant p.Arg1190Gln
22 21167698 chr22:21167698 T G 1 0.00052 PI4KA missense variant p.Thr318Lys
22 21384134 rs371746371 G C 1 0.00054 SLC7A4 missense variant p.Val497Leu
22 22312884 chr22:22312884 T G 1 0.00056 TOP3B missense variant p.Pro696His
22 24437627 chr22:24437627 T C 1 0.00052 CABIN1 missense variant p.Pro84Leu
missense variant &
22 24492045 rs745725059 G A 1 0.00052 CABIN1 splice region variant p.Lys1313Arg
22 26895183 rs751102347 C T 1 0.00052 TFIP11 missense variant p.Thr406Ala
22 30057288 rs753300935 T C 1 0.00052 NF2 missense variant p.Pro257Leu
22 30189580 rs775679720 T C 1 0.00058 ASCC2 missense variant p.Val592Met
22 30508498 chr22:30508498 A C 1 0.00053 HORMAD2 missense variant p.Pro110His
22 30866505 chr22:30866505 A C 1 0.00052 SEC14L3 missense variant p.Arg40Leu
22 32498054 chr22:32498054 T C 1 0.00052 SLC5A1 missense variant p.Arg499Cys
22 37865907 chr22:37865907 G A 1 0.00054 MFNG missense variant p.Ile71Thr
22 40283748 rs766301195 A G 1 0.00052 ENTHD1 missense variant p.Ala2Val
22 41660778 chr22:41660778 G A 1 0.00056 RANGAP1 missense variant p.Phe124Leu
22 42262870 rs752927725 C T 1 0.00052 SREBF2 missense variant p.Phe42Leu
22 46654517 chr22:46654517 T G 1 0.00052 PKDREJ missense variant p.Pro1568His
22 50279232 chr22:50279232 C T 1 0.00053 ZBED4 missense variant p.Phe641Ser
22 50279355 chr22:50279355 G A 1 0.00052 ZBED4 missense variant p.Asn682Ser
22 50488649 chr22:50488649 A G 1 0.00052 TTLL8 missense variant p.His63Tyr
22 50678670 chr22:50678670 T C 1 0.00054 TUBGCP6 missense variant p.Glu290Lys
22 50682428 chr22:50682428 T C 1 0.00052 TUBGCP6 missense variant p.Ser154Asn
23 12939607 chrX:12939607 A T 1 0.00056 TLR8 missense variant p.Ser834Arg

23 30322733 chrX:30322733 C T 1 0.00056 NR0B1 missense variant p.Asp459Gly

23 38535020 rs201317934 G A 1 0.00056 TM4SF2 missense variant p.His198Arg
23 41060529 rs773181993 G A 1 0.00056 USP9X missense variant p.Asn1607Ser
23 47517190 chrX:47517190 A C 1 0.00056 UXT missense variant p.Glu69Asp
23 49032152 chrX:49032152 A T 1 0.00058 PRICKLE3 missense variant p.His585Leu
23 49050780 chrX:49050780 T C 1 0.00057 SYP missense variant p.Gly89Glu
23 70787374 chrX:70787374 A G 1 0.00056 OGT missense variant p.Val872Ile
23 77388925 chrX:77388925 G C 1 0.00056 TAF9B missense variant p.Val168Leu
missense variant &
23 100537441 chrX:100537441 A T 1 0.00057 TAF7L splice region variant p.Met180Leu
23 101912859 chrX:101912859 T G 1 0.00057 GPRASP1 missense variant p.Ala1340Ser
23 101970975 rs775866009 T C 1 0.00056 GPRASP2 missense variant p.Ala393Val
23 107316048 chrX:107316048 C T 1 0.00056 VSIG1 missense variant p.Val221Ala
23 107433643 rs200541162 T G 1 0.00056 COL4A6 missense variant p.Leu470Ile
23 107811862 rs779822354 T C 1 0.00056 COL4A5 missense variant p.Pro94Ser
23 107976892 chrX:107976892 C T 1 0.00058 IRS4 missense variant p.Ile895Val
23 114141252 rs201583846 C T 1 0.00056 HTR2C missense variant p.Trp186Arg
23 117895129 chrX:117895129 A C 1 0.00057 IL13RA1 missense variant p.Asn235Lys
23 123515051 rs774434990 A G 1 0.00056 TENM1 missense variant p.Arg2512Trp
23 129171505 rs368783964 T C 1 0.00062 BCORL1 missense variant p.Thr1564Met
23 153699965 rs781972979 G C 1 0.00059 PLXNA3 missense variant p.Thr1835Ser
23 153774301 chrX:153774301 T C 1 0.00057 G6PD missense variant p.Asp24Asn
23 153944424 rs147290916 T C 1 0.00057 GAB3 missense variant p.Val85Met
23 154009930 chrX:154009930 A G 1 0.00056 MPP1 missense variant p.Thr365Ile

Supplementary Table S12. Clinical data for the five Swedish SLE patients carrying the MUC5B rs773068050 missense case-only allele.
SLE1 SLE2 SLE3 SLE4 SLE5

Gender Female Female Male Female Female
Age at diagnosis 30 43 50 27 48
Age at follow-up 34 77 50 33 64
≥4 ACR criteria (Tan et al., 1982; Hochberg et al., 1997) YES YES YES YES YES
Number of ACR criteria fulfilled 7 4 7 4 5
ACR criteria:
1) Malar rash YES YES NO NO NO
2) Discoid rash NO NO NO NO NO
3) Photosensitivity YES NO NO NO YES
4) Oral Ulcers NO NO YES NO NO
5) Arthritis YES YES YES YES YES
6) Serositis YES NO YES NO YES
7) Renal disorder YES YES YES NO NO
Class* IV III V NA NA
8) Neurologic disorder NO NO NO NO NO
9) Hematologic disorder NO NO YES YES YES
10) Immunologic disorder YES NO YES YES NO
11) Positive ANA YES YES YES YES YES
Autoantibodies:
Anti-DNA YES NO YES YES NO
Anti-Sm NO NO YES NO NO
Anti-RNP NO NO YES NA NA
Anti-SSA NO NO YES NO YES
Anti-SSB NO NO YES NO NO
Anti-cardiolipin IgG NO NO NO NO YES
Anti-beta2-glycoprotein I IgG YES NO NO NO YES
Rheumatoid factor (RF) NO NO NO NA NA
Lupus anticoagulant (LAC) NO NO NO NA NA
SLICC Damage Index (Gladman et al., 1996) 1 5 1 0 3
Lung involvement:
Interstitial lung disease (ILD) clinical diagnosis NO NO NO NO NO
CT-scan performed NO NO YES NO NO
Chest x-ray performed YES, several (lung x-ray) YES YES YES YES
Other lung disease/symptoms Relapsing pleuritis Asthma Pleuritis previously; NO NO
breathlessness currently;
emphysema (lower lobes);
air trappning (upper lobes)
ACR: the American College of Rheumatology
SLICC: The Systemic Lupus Erythematosus International Collaborating Clinics
NA: not available
*Biopsies were classified according to the WHO or the ISN/RPS 2003 classification systems

MOLECULAR PATHWAYS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

REVEALED BY GENE CENTRED DNA SEQUENCING
Sandling et al.
Contents:
Supplementary Figures S1-S8





Supplementary Figure S3. Pathway polygenic risk score density plots for SLE patients and controls for each tested KEGG pathway. P-values represent
differences in PRS between SLE patients (SLE) and control individuals (HC), uncorrected P-values are presented (Bonferroni corrected threshold P=0.00143).
The dashed line indicates the PRS 97.5 percentile in control individuals.



Supplementary Figure S4. Pathway SLE polygenic risk score density plots for the four groups of SLE patients identified for each tested KEGG pathway. P-
values represent differences in PRS between clusters of SLE patients, uncorrected P-values are presented (Bonferroni corrected threshold P=0.00143).

Supplementary Figure S5. Results of SLE case-control association analyses with P-values for
association plotted against chromosomal location: a) Gene-based aggregate association testing
(SKAT-O) where each point represents a gene region. Gene names are indicated for the top gene
regions. The red line represents a Bonferroni corrected significance threshold and the black line FDR
0.05. Novel loci are indicated in bold. b) Single variant association testing where each point
represents a SNV. The red line represents a Bonferroni corrected significance threshold and the black
line the suggestive significance threshold (P<1×10-4). Novel loci are indicated in bold. c-e) Single
variant association result regional association plots for the CAPN13, MOB3B/IFNK and HAL regions
respectively. The colour scale indicates linkage disequilibrium (r2) between SNVs.

Supplementary Figure S6. Distribution of different classes of SNVs in SLE patients and control
individuals: a) rare non-synonymous variants, b) rare synonymous variants, c) rare constrained
variants (GERP RS score >2), d) rare non-coding variants (any of the following snpeff annotations:
sequence feature, upstream, downstream, intergenic, TF binding site variant). P-values represent
difference between SLE patients and control individuals, uncorrected P-values are presented
(Bonferroni corrected threshold P=0.0125).

Supplementary Figure S7. Genetic population structure of study individuals. a) Study samples
mapped on population reference samples. b) Principal components for population stratification
within study, PC1 vs PC2 c) PC2 vs PC3 d) PC3 vs PC4.

Supplementary Figure S8. SNV genotype average concordance between targeted sequencing and
genotyping by a beadchip array (Illumina ImmunoChip). Concordance for two types of SNVs, common
SNVs (MAF≥0.05) and low frequency SNVs (MAF<0.05), are displayed.

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University of Southern Denmark

Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred

Citation for pulished version (APA):

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• You may download this work for personal use only.

Molecular pathways in patients with systemic lupus

Handling editor Josef S ABSTRACT

DISCUSSION option in a subset of patients with SLE.34 Conversely, low-­dose

Table 3 SLE case-­only recurrent non-­synonymous SNVs

6 Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi:10.1136/annrheumdis-2020-218636

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi:10.1136/annrheumdis-2020-218636 7

8 Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi:10.1136/annrheumdis-2020-218636

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi:10.1136/annrheumdis-2020-218636 9

MOLECULAR PATHWAYS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS REVEALED BY

Supplementary Materials and Methods

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

Supplementary Materials and Methods

Subjects and DNA samples

2015/450 and 2016/155).

Targeted DNA sequencing

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

Alignment and variant calling

Sample and variant level quality control

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

had a minimum call rate of 80%.

Hardy-Weinberg equilibrium (P <1x10-6, calculated on controls) were excluded as well as

supplementary Figure S8).

Variant level annotation

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

to upstream, downstream, intergenic regions or regions overlapping transcription factor binding

was defined as from the gene SCGN to SYNGAP1 on hg19 chr6:25,652,429-33,560,852.(17)

Single variant analyses

Laboratory(23) or in the Genome Aggregation Database (gnomAD) European non-Finnish controls

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

Aggregate association testing

disease (31) were grouped into separate gene sets.

inclusion of the first three principal components generated in EIGENSOFT as covariates.(32) We

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

protein level scores) annotations were presented.(35, 36)

Risk scores and cluster analysis

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

Replication study and meta-analysis

extracted/imputed from existing sequencing or GWAS array data.

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

1,211 control individuals.

3,241 control individuals.

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

23. Ameur A, Dahlberg J, Olason P, et al. SweGen: a whole-genome data resource of

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

Supplementary Table S1a. Patient characteristics Scandinavian SLE cohorts.

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

Pathway (KEGG ID) Genes (RefSeq)

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

Sandling JK, et al. Ann Rheum Dis 2020;0:1–9. doi: 10.1136/annrheumdis-2020-218636

N SLE SNVs N patients Percent patients

DISCUSSION option in a subset of patients with SLE.34 Conversely, low-dose

Table 3 SLE case-only recurrent non-synonymous SNVs