Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, pot... more Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter th...
To dissect the genetic architecture of blood pressure and assess effects on target organ damage, ... more To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond th...
We have analysed the sequence organization of the pseudoautosomal region at the telomeres of the ... more We have analysed the sequence organization of the pseudoautosomal region at the telomeres of the long arms of the human sex chromosomes and shown that it is 320 kb long. A LINE sequence is present on both the X and Y chromosomes immediately adjacent to the breakpoint in homology suggesting that the homology arose as a result of an ectopic recombination event mediated by LINE sequences originally present in non-homologous stretches of X and Y chromosomal DNA. This led to the translocation of sequences from the X chromosome telomere onto the Y chromosome and created a new pseudoautosomal region.
Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity... more Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute t...
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain lar... more Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P…
Research in modern biomedicine and social science requires sample sizes so large that they can of... more Research in modern biomedicine and social science requires sample sizes so large that they can often only be achieved through a pooled co-analysis of data from several studies. But the pooling of information from individuals in a central database that may be queried by researchers raises important ethico-legal questions and can be controversial. In the UK this has been highlighted by recent debate and controversy relating to the UK's proposed…
The genetic diversity and relationships among 154 Bacillus cereus /B. thuringiensis isolates reco... more The genetic diversity and relationships among 154 Bacillus cereus /B. thuringiensis isolates recovered from soil samples from five geographic areas in Norway were investigated with multilocus enzyme electrophoresis (MEE). Cluster analysis revealed two major groups (designated cluster I and cluster II) separated at genetic distance greater than 0.55. Cluster I included 62 electrophoretic types (ETs) originating from all five locations, whereas, in cluster II, all but one isolate were from the same location. The isolates were also serotyped with B. thuringiensis flagellar antisera, and 28 distinct serotypes were identified. In general, serotyping did not show correlation to the genetic diversity of the isolates. The presence of IS231-and IS240-like transposable elements was detected in 14% of the strains of cluster II only. Parasporal crystals were observed in three strains; ten other strains were toxic to Trichoplusia ni. We conclude that B. cereus/B. thuringiensis from soil exhibit a high degree of recombination. Bacillus cereus and B. thuringiensis are Gram-positive, spore-forming bacteria commonly found in soil [8]. B. thuringiensis is phenotypically distinguished from B. cereus only by the presence of intracellular protein crystals during sporulation. We have recently shown, using a limited number of laboratory strains, that B. thuringiensis and B. cereus are essentially identical [5-7]. The present study was undertaken to analyze the genetic diversity of B. cereus / B. thuringiensis in their natural environment, the soil. In order to evaluate the genetic diversity within and between soil samples, bacterial isolates were collected from a few selected areas in Norway, 400 to 1200 km apart. For this analysis, multilocus enzyme electrophoresis (MEE) was used as a convenient method to assess allelic diversity in natural populations of bacteria [28]. In contrast to serotyping, where variation in only one or a few antigenic determinants is monitored, MEE gives information about allelic variation of randomly selected genes coding for metabolic enzymes. However, since serotyping is a well-established method for B. thuringiensis strain identification, the isolated strains were also serotyped. We also included toxicity assays against larvae of the lepidoptera Trichoplusia ni, known to be sensitive to Cry toxins such as CryIA [31]. Finally, since the mobile elements IS231, IS232, and IS240 were found associated with various cry genes [22], their distribution among the natural isolates was also investigated. Materials and Methods Strain isolation. In total, 154 strains were isolated from soil samples in five locations in Norway (Fig. 1): Moss (Østfold), 77 strains from four sample sites, all sample sites were on the Southern part of Jeløy island in Moss; Singsås (Sør-Trøndelag), 24 strains; Brekkvasselv (Nord-Trøndelag), 15 strains; Steigen (Nordland), 14 strains; and Tromsø (Troms), 24 strains, the sample site was on the Tromsø island. Samples from Moss were taken in September, the others about one month earlier. Strains isolated in Tromsø, Singsås, and Steigen were from heather soil, and in Brekkvasselv from a woodland at riverside. The four soil sampling sites from Moss were taken from a leaf and grass compost (sample 1, 6 strains), a strawberry field (sample 2, 25 strains), a
Background: Not all obese subjects have an adverse metabolic profile predisposing them to develop... more Background: Not all obese subjects have an adverse metabolic profile predisposing them to developing type 2 diabetes or cardiovascular disease. The BioSHaRE-EU Healthy Obese Project aims to gain insights into the consequences of (healthy) obesity using data on risk factors and phenotypes across several large-scale cohort studies. Aim of this study was to describe the prevalence of obesity, metabolic syndrome (MetS) and metabolically healthy obesity (MHO) in ten participating studies. Methods: Ten different cohorts in seven countries were combined, using data transformed into a harmonized format. All participants were of European origin, with age 18-80 years. They had participated in a clinical examination for anthropometric and blood pressure measurements. Blood samples had been drawn for analysis of lipids and glucose. Presence of MetS was assessed in those with obesity (BMI ≥ 30 kg/m 2) based on the 2001 NCEP ATP III criteria, as well as an adapted set of less strict criteria. MHO was defined as obesity, having none of the MetS components, and no previous diagnosis of cardiovascular disease. Results: Data for 163,517 individuals were available; 17% were obese (11,465 men and 16,612 women). The prevalence of obesity varied from 11.6% in the Italian CHRIS cohort to 26.3% in the German KORA cohort. The age-standardized percentage of obese subjects with MetS ranged in women from 24% in CHRIS to 65% in the Finnish Health2000 cohort, and in men from 43% in CHRIS to 78% in the Finnish DILGOM cohort, with elevated blood pressure the most frequently occurring factor contributing to the prevalence of the metabolic syndrome. The age-standardized prevalence of MHO varied in women from 7% in Health2000 to 28% in NCDS, and in men from 2% in DILGOM to 19% in CHRIS. MHO was more prevalent in women than in men, and decreased with age in both sexes.
Individual-level data pooling of large population-based studies across research centres in intern... more Individual-level data pooling of large population-based studies across research centres in international research projects faces many hurdles. The BioSHaRE (Biobank Standardisation and Harmonisation for Research Excellence in the European Union) project aims to address these issues by building a collaborative group of investigators and developing tools for data harmonization, database integration and federated data analyses. Eight population-based studies in six European countries were recruited to participate in the BioSHaRE project. Through workshops, teleconferences and electronic communications, participating investigators identified a set of 96 variables targeted for harmonization to answer research questions of interest. Using each study's questionnaires, standard operating procedures, and data dictionaries, harmonization potential was assessed. Whenever harmonization was deemed possible, processing algorithms were developed and implemented in an open-source software infra...
The arctic fox (Alopex lagopus) in Scandinavia is classified as critically endangered after havin... more The arctic fox (Alopex lagopus) in Scandinavia is classified as critically endangered after having gone through a severe decline in population size in the beginning of the 20th century, from which it has failed to recover despite more than 65 years of protection. Arctic foxes have a high dispersal rate and often disperse over long distances, suggesting that there was probably little population differentiation within Scandinavia prior to the bottleneck. It is, however, possible that the recent decline in population size has led to a decrease in dispersal and an increase in population fragmentation. To examine this, we used 10 microsatellite loci to analyse genetic variation in 150 arctic foxes from Scandinavia and Russia. The results showed that the arctic fox in Scandinavia presently is subdivided into four populations, and that the Kola Peninsula and northwest Russia together form a large fifth population. Current dispersal between the populations seemed to be very low, but genetic variation within them was relatively high. This and the relative F ST values among the populations are consistent with a model of recent fragmentation within Scandinavia. Since the amount of genetic variation is high within the populations, but the populations are small and isolated, demographic stochasticity seems to pose a higher threat to the populations' persistence than inbreeding depression and low genetic variation.
Previous studies have indicated that the latent autoimmune diabetes in adults (LADA) phenotype is... more Previous studies have indicated that the latent autoimmune diabetes in adults (LADA) phenotype is heterogeneous and that LADA patients share features of type 1 and type 2 diabetes in various proportions. We tested for association of known type 1 and type 2 diabetes susceptibility genes in LADA subjects and analyzed relationships to a marker of autoimmune activity (titers of anti-GAD) and a phenotypic risk factor of type 2 diabetes (BMI). Data were assembled from the Nord-Trøndelag Health Study (HUNT) study, which comprises the adult population of an entire county in Norway. We genotyped 60 single nucleotide polymorphisms (SNPs) known to be associated with type 1 or type 2 diabetes, including 14 tag SNPs used for HLA haplotyping in 120 type 1 diabetic, 126 LADA, and 1,090 type 2 diabetic patients and 1,503 age- and sex-matched nondiabetic subjects. The majority of the strongly associated HLA haplotypes for type 1 diabetes were significantly associated with LADA in general, but mainly...
Eurasian otter populations strongly declined and partially disappeared due to global and local ca... more Eurasian otter populations strongly declined and partially disappeared due to global and local causes (habitat destruction, water pollution, human persecution) in parts of their continental range. Conservation strategies, based on reintroduction projects or restoration of dispersal corridors, should rely on sound knowledge of the historical or recent consequences of population genetic structuring. Here we present the results of a survey performed on 616 samples, collected from 19 European countries, genotyped at the mtDNA control-region and 11 autosomal microsatellites. The mtDNA variability was low (nucleotide diversity = 0.0014; average number of pairwise differences = 2.25), suggesting that extant otter mtDNA lineages originated recently. A star-shaped mtDNA network did not allow outlining any phylogeographic inference. Microsatellites were only moderately variable (H o = 0.50; H e = 0.58, on average across populations), the average allele number was low (observed A o = 4.9, range 2.5-6.8; effective A e = 2.8; range 1.6-3.7), suggesting small historical effective population size. Extant otters likely originated from the expansion of a single refugial population. Bayesian clustering and landscape genetic analyses however indicate that local populations are genetically differentiated, perhaps as consequence of post-glacial demographic fluctuations and recent isolation. These results delineate a framework that should be used for implementing conservation programs in Europe, particularly if they are based on the reintroduction of wild or captive-reproduced otters.
Research in modern biomedicine and social science requires sample sizes so large that they can of... more Research in modern biomedicine and social science requires sample sizes so large that they can often only be achieved through a pooled co-analysis of data from several studies. But the pooling of information from individuals in a central database that may be queried by researchers raises important ethico-legal questions and can be controversial. In the UK this has been highlighted by recent debate and controversy relating to the UK's proposed 'care.data' initiative, and these issues reflect important societal and professional concerns about privacy, confidentiality and intellectual property. DataSHIELD provides a novel technological solution that can circumvent some of the most basic challenges in facilitating the access of researchers and other healthcare professionals to individual-level data. Commands are sent from a central analysis computer (AC) to several data computers (DCs) storing the data to be co-analysed. The data sets are analysed simultaneously but in paral...
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic conseque... more Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex...
Eurasian otter populations strongly declined and partially disappeared due to global and local ca... more Eurasian otter populations strongly declined and partially disappeared due to global and local causes (habitat destruction, water pollution, human persecution) in parts of their continental range. Conservation strategies, based on reintroduction projects or restoration of dispersal corridors, should rely on sound knowledge of the historical or recent consequences of population genetic structuring. Here we present the results of a survey performed on 616 samples, collected from 19 European countries, genotyped at the mtDNA control-region and 11 autosomal microsatellites. The mtDNA variability was low (nucleotide diversity = 0.0014; average number of pairwise differences = 2.25), suggesting that extant otter mtDNA lineages originated recently. A star-shaped mtDNA network did not allow outlining any phylogeographic inference. Microsatellites were only moderately variable (H o = 0.50; H e = 0.58, on average across populations), the average allele number was low (observed A o = 4.9, range 2.5-6.8; effective A e = 2.8; range 1.6-3.7), suggesting small historical effective population size. Extant otters likely originated from the expansion of a single refugial population. Bayesian clustering and landscape genetic analyses however indicate that local populations are genetically differentiated, perhaps as consequence of post-glacial demographic fluctuations and recent isolation. These results delineate a framework that should be used for implementing conservation programs in Europe, particularly if they are based on the reintroduction of wild or captive-reproduced otters.
Background: Not all obese subjects have an adverse metabolic profile predisposing them to develop... more Background: Not all obese subjects have an adverse metabolic profile predisposing them to developing type 2 diabetes or cardiovascular disease. The BioSHaRE-EU Healthy Obese Project aims to gain insights into the consequences of (healthy) obesity using data on risk factors and phenotypes across several large-scale cohort studies. Aim of this study was to describe the prevalence of obesity, metabolic syndrome (MetS) and metabolically healthy obesity (MHO) in ten participating studies. Methods: Ten different cohorts in seven countries were combined, using data transformed into a harmonized format. All participants were of European origin, with age 18-80 years. They had participated in a clinical examination for anthropometric and blood pressure measurements. Blood samples had been drawn for analysis of lipids and glucose. Presence of MetS was assessed in those with obesity (BMI ≥ 30 kg/m 2 ) based on the 2001 NCEP ATP III criteria, as well as an adapted set of less strict criteria. MHO was defined as obesity, having none of the MetS components, and no previous diagnosis of cardiovascular disease.
Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, pot... more Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter th...
To dissect the genetic architecture of blood pressure and assess effects on target organ damage, ... more To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond th...
We have analysed the sequence organization of the pseudoautosomal region at the telomeres of the ... more We have analysed the sequence organization of the pseudoautosomal region at the telomeres of the long arms of the human sex chromosomes and shown that it is 320 kb long. A LINE sequence is present on both the X and Y chromosomes immediately adjacent to the breakpoint in homology suggesting that the homology arose as a result of an ectopic recombination event mediated by LINE sequences originally present in non-homologous stretches of X and Y chromosomal DNA. This led to the translocation of sequences from the X chromosome telomere onto the Y chromosome and created a new pseudoautosomal region.
Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity... more Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute t...
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain lar... more Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P…
Research in modern biomedicine and social science requires sample sizes so large that they can of... more Research in modern biomedicine and social science requires sample sizes so large that they can often only be achieved through a pooled co-analysis of data from several studies. But the pooling of information from individuals in a central database that may be queried by researchers raises important ethico-legal questions and can be controversial. In the UK this has been highlighted by recent debate and controversy relating to the UK's proposed…
The genetic diversity and relationships among 154 Bacillus cereus /B. thuringiensis isolates reco... more The genetic diversity and relationships among 154 Bacillus cereus /B. thuringiensis isolates recovered from soil samples from five geographic areas in Norway were investigated with multilocus enzyme electrophoresis (MEE). Cluster analysis revealed two major groups (designated cluster I and cluster II) separated at genetic distance greater than 0.55. Cluster I included 62 electrophoretic types (ETs) originating from all five locations, whereas, in cluster II, all but one isolate were from the same location. The isolates were also serotyped with B. thuringiensis flagellar antisera, and 28 distinct serotypes were identified. In general, serotyping did not show correlation to the genetic diversity of the isolates. The presence of IS231-and IS240-like transposable elements was detected in 14% of the strains of cluster II only. Parasporal crystals were observed in three strains; ten other strains were toxic to Trichoplusia ni. We conclude that B. cereus/B. thuringiensis from soil exhibit a high degree of recombination. Bacillus cereus and B. thuringiensis are Gram-positive, spore-forming bacteria commonly found in soil [8]. B. thuringiensis is phenotypically distinguished from B. cereus only by the presence of intracellular protein crystals during sporulation. We have recently shown, using a limited number of laboratory strains, that B. thuringiensis and B. cereus are essentially identical [5-7]. The present study was undertaken to analyze the genetic diversity of B. cereus / B. thuringiensis in their natural environment, the soil. In order to evaluate the genetic diversity within and between soil samples, bacterial isolates were collected from a few selected areas in Norway, 400 to 1200 km apart. For this analysis, multilocus enzyme electrophoresis (MEE) was used as a convenient method to assess allelic diversity in natural populations of bacteria [28]. In contrast to serotyping, where variation in only one or a few antigenic determinants is monitored, MEE gives information about allelic variation of randomly selected genes coding for metabolic enzymes. However, since serotyping is a well-established method for B. thuringiensis strain identification, the isolated strains were also serotyped. We also included toxicity assays against larvae of the lepidoptera Trichoplusia ni, known to be sensitive to Cry toxins such as CryIA [31]. Finally, since the mobile elements IS231, IS232, and IS240 were found associated with various cry genes [22], their distribution among the natural isolates was also investigated. Materials and Methods Strain isolation. In total, 154 strains were isolated from soil samples in five locations in Norway (Fig. 1): Moss (Østfold), 77 strains from four sample sites, all sample sites were on the Southern part of Jeløy island in Moss; Singsås (Sør-Trøndelag), 24 strains; Brekkvasselv (Nord-Trøndelag), 15 strains; Steigen (Nordland), 14 strains; and Tromsø (Troms), 24 strains, the sample site was on the Tromsø island. Samples from Moss were taken in September, the others about one month earlier. Strains isolated in Tromsø, Singsås, and Steigen were from heather soil, and in Brekkvasselv from a woodland at riverside. The four soil sampling sites from Moss were taken from a leaf and grass compost (sample 1, 6 strains), a strawberry field (sample 2, 25 strains), a
Background: Not all obese subjects have an adverse metabolic profile predisposing them to develop... more Background: Not all obese subjects have an adverse metabolic profile predisposing them to developing type 2 diabetes or cardiovascular disease. The BioSHaRE-EU Healthy Obese Project aims to gain insights into the consequences of (healthy) obesity using data on risk factors and phenotypes across several large-scale cohort studies. Aim of this study was to describe the prevalence of obesity, metabolic syndrome (MetS) and metabolically healthy obesity (MHO) in ten participating studies. Methods: Ten different cohorts in seven countries were combined, using data transformed into a harmonized format. All participants were of European origin, with age 18-80 years. They had participated in a clinical examination for anthropometric and blood pressure measurements. Blood samples had been drawn for analysis of lipids and glucose. Presence of MetS was assessed in those with obesity (BMI ≥ 30 kg/m 2) based on the 2001 NCEP ATP III criteria, as well as an adapted set of less strict criteria. MHO was defined as obesity, having none of the MetS components, and no previous diagnosis of cardiovascular disease. Results: Data for 163,517 individuals were available; 17% were obese (11,465 men and 16,612 women). The prevalence of obesity varied from 11.6% in the Italian CHRIS cohort to 26.3% in the German KORA cohort. The age-standardized percentage of obese subjects with MetS ranged in women from 24% in CHRIS to 65% in the Finnish Health2000 cohort, and in men from 43% in CHRIS to 78% in the Finnish DILGOM cohort, with elevated blood pressure the most frequently occurring factor contributing to the prevalence of the metabolic syndrome. The age-standardized prevalence of MHO varied in women from 7% in Health2000 to 28% in NCDS, and in men from 2% in DILGOM to 19% in CHRIS. MHO was more prevalent in women than in men, and decreased with age in both sexes.
Individual-level data pooling of large population-based studies across research centres in intern... more Individual-level data pooling of large population-based studies across research centres in international research projects faces many hurdles. The BioSHaRE (Biobank Standardisation and Harmonisation for Research Excellence in the European Union) project aims to address these issues by building a collaborative group of investigators and developing tools for data harmonization, database integration and federated data analyses. Eight population-based studies in six European countries were recruited to participate in the BioSHaRE project. Through workshops, teleconferences and electronic communications, participating investigators identified a set of 96 variables targeted for harmonization to answer research questions of interest. Using each study's questionnaires, standard operating procedures, and data dictionaries, harmonization potential was assessed. Whenever harmonization was deemed possible, processing algorithms were developed and implemented in an open-source software infra...
The arctic fox (Alopex lagopus) in Scandinavia is classified as critically endangered after havin... more The arctic fox (Alopex lagopus) in Scandinavia is classified as critically endangered after having gone through a severe decline in population size in the beginning of the 20th century, from which it has failed to recover despite more than 65 years of protection. Arctic foxes have a high dispersal rate and often disperse over long distances, suggesting that there was probably little population differentiation within Scandinavia prior to the bottleneck. It is, however, possible that the recent decline in population size has led to a decrease in dispersal and an increase in population fragmentation. To examine this, we used 10 microsatellite loci to analyse genetic variation in 150 arctic foxes from Scandinavia and Russia. The results showed that the arctic fox in Scandinavia presently is subdivided into four populations, and that the Kola Peninsula and northwest Russia together form a large fifth population. Current dispersal between the populations seemed to be very low, but genetic variation within them was relatively high. This and the relative F ST values among the populations are consistent with a model of recent fragmentation within Scandinavia. Since the amount of genetic variation is high within the populations, but the populations are small and isolated, demographic stochasticity seems to pose a higher threat to the populations' persistence than inbreeding depression and low genetic variation.
Previous studies have indicated that the latent autoimmune diabetes in adults (LADA) phenotype is... more Previous studies have indicated that the latent autoimmune diabetes in adults (LADA) phenotype is heterogeneous and that LADA patients share features of type 1 and type 2 diabetes in various proportions. We tested for association of known type 1 and type 2 diabetes susceptibility genes in LADA subjects and analyzed relationships to a marker of autoimmune activity (titers of anti-GAD) and a phenotypic risk factor of type 2 diabetes (BMI). Data were assembled from the Nord-Trøndelag Health Study (HUNT) study, which comprises the adult population of an entire county in Norway. We genotyped 60 single nucleotide polymorphisms (SNPs) known to be associated with type 1 or type 2 diabetes, including 14 tag SNPs used for HLA haplotyping in 120 type 1 diabetic, 126 LADA, and 1,090 type 2 diabetic patients and 1,503 age- and sex-matched nondiabetic subjects. The majority of the strongly associated HLA haplotypes for type 1 diabetes were significantly associated with LADA in general, but mainly...
Eurasian otter populations strongly declined and partially disappeared due to global and local ca... more Eurasian otter populations strongly declined and partially disappeared due to global and local causes (habitat destruction, water pollution, human persecution) in parts of their continental range. Conservation strategies, based on reintroduction projects or restoration of dispersal corridors, should rely on sound knowledge of the historical or recent consequences of population genetic structuring. Here we present the results of a survey performed on 616 samples, collected from 19 European countries, genotyped at the mtDNA control-region and 11 autosomal microsatellites. The mtDNA variability was low (nucleotide diversity = 0.0014; average number of pairwise differences = 2.25), suggesting that extant otter mtDNA lineages originated recently. A star-shaped mtDNA network did not allow outlining any phylogeographic inference. Microsatellites were only moderately variable (H o = 0.50; H e = 0.58, on average across populations), the average allele number was low (observed A o = 4.9, range 2.5-6.8; effective A e = 2.8; range 1.6-3.7), suggesting small historical effective population size. Extant otters likely originated from the expansion of a single refugial population. Bayesian clustering and landscape genetic analyses however indicate that local populations are genetically differentiated, perhaps as consequence of post-glacial demographic fluctuations and recent isolation. These results delineate a framework that should be used for implementing conservation programs in Europe, particularly if they are based on the reintroduction of wild or captive-reproduced otters.
Research in modern biomedicine and social science requires sample sizes so large that they can of... more Research in modern biomedicine and social science requires sample sizes so large that they can often only be achieved through a pooled co-analysis of data from several studies. But the pooling of information from individuals in a central database that may be queried by researchers raises important ethico-legal questions and can be controversial. In the UK this has been highlighted by recent debate and controversy relating to the UK's proposed 'care.data' initiative, and these issues reflect important societal and professional concerns about privacy, confidentiality and intellectual property. DataSHIELD provides a novel technological solution that can circumvent some of the most basic challenges in facilitating the access of researchers and other healthcare professionals to individual-level data. Commands are sent from a central analysis computer (AC) to several data computers (DCs) storing the data to be co-analysed. The data sets are analysed simultaneously but in paral...
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic conseque... more Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex...
Eurasian otter populations strongly declined and partially disappeared due to global and local ca... more Eurasian otter populations strongly declined and partially disappeared due to global and local causes (habitat destruction, water pollution, human persecution) in parts of their continental range. Conservation strategies, based on reintroduction projects or restoration of dispersal corridors, should rely on sound knowledge of the historical or recent consequences of population genetic structuring. Here we present the results of a survey performed on 616 samples, collected from 19 European countries, genotyped at the mtDNA control-region and 11 autosomal microsatellites. The mtDNA variability was low (nucleotide diversity = 0.0014; average number of pairwise differences = 2.25), suggesting that extant otter mtDNA lineages originated recently. A star-shaped mtDNA network did not allow outlining any phylogeographic inference. Microsatellites were only moderately variable (H o = 0.50; H e = 0.58, on average across populations), the average allele number was low (observed A o = 4.9, range 2.5-6.8; effective A e = 2.8; range 1.6-3.7), suggesting small historical effective population size. Extant otters likely originated from the expansion of a single refugial population. Bayesian clustering and landscape genetic analyses however indicate that local populations are genetically differentiated, perhaps as consequence of post-glacial demographic fluctuations and recent isolation. These results delineate a framework that should be used for implementing conservation programs in Europe, particularly if they are based on the reintroduction of wild or captive-reproduced otters.
Background: Not all obese subjects have an adverse metabolic profile predisposing them to develop... more Background: Not all obese subjects have an adverse metabolic profile predisposing them to developing type 2 diabetes or cardiovascular disease. The BioSHaRE-EU Healthy Obese Project aims to gain insights into the consequences of (healthy) obesity using data on risk factors and phenotypes across several large-scale cohort studies. Aim of this study was to describe the prevalence of obesity, metabolic syndrome (MetS) and metabolically healthy obesity (MHO) in ten participating studies. Methods: Ten different cohorts in seven countries were combined, using data transformed into a harmonized format. All participants were of European origin, with age 18-80 years. They had participated in a clinical examination for anthropometric and blood pressure measurements. Blood samples had been drawn for analysis of lipids and glucose. Presence of MetS was assessed in those with obesity (BMI ≥ 30 kg/m 2 ) based on the 2001 NCEP ATP III criteria, as well as an adapted set of less strict criteria. MHO was defined as obesity, having none of the MetS components, and no previous diagnosis of cardiovascular disease.
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Papers by K. Kvaloy