Práctica 9

RECONOCIMIENTO DE CÉLULAS EUCARIÓTICAS III: VEGETALES

I. FUNDAMENTO TEÓRICO:
REINO VEGETAL

Fanerógamas Criptógamas

Angiosperma Gimnosperma Briofitas Pteridofitas

Monocotiledones Dicotiledones Musgos Filicíneas

Hepáticas Licopodios
Equisetos

1. DEFINICIÓN:
Las plantas o vegetales son organismos eucariontes, multicelulares, autótrofos fotosintéticos, cuyas
células poseen pared celular de celulosa y almacenan almidón en el interior de sus plastidios.
Su importancia radica en que producen oxígeno atmosférico; son fuente de alimento para los organismos
heterótrofos, sirven
de albergue para di-
ferentes organis- ¿Cuáles son las partes de una planta?
mos como insectos
y aves; además es Las hojas ELl tallo
tallo
importante su apor- Son los principales órganos Corresponde
fotosintéticos de casi todas Envés a la parte aérea
te en sustancias las plantas. y central de las
Base
medicinales, esen- plantas que
Vaina sostienen a las
cias, resinas, etc. Ápice
Haz ramas o tallos
secundarios, a
Limbo
Pecíolo las hojas y a
Borde Nervadura veces a las flores
2. PART ES DE LA
y frutos.
PLANTA En el tallo se distinguen:
Los órganos de las La raíz Entrenudos
Constituyen el órgano de
plantas con flores las plantas superiores, Yemas
son la raíz, el tallo, casi siempre subterráneo,
que desempeña varias funciones, Nudos
las hojas, las flores
entre ellas absorber y conducir
y los frutos; los tres agua y minerales disueltos,
primeros cumplen la acumular nutrientes y sujetar
función de nutrición la planta al suelo. En la raíz se Cuello
Las raíces de muchas plantas distinguen:
y los dos órganos
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son comestibles de sustancias

restantes, de repro- nutritivas, en particular almidón.
ducción. Entre las de importancia agrícola Zona pilífera
destacan el camote, la remolacha Zona de crecimiento
azucarera, el nabo, la zanahoria, Zona de
y la yuca. ramificaciones Cofia o Piloriza

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Biología celular y molecular
 3. ORGANOGRAFÍA VEGETAL:
ORGANOGRAFÍA VEGETAL

Pueden ser

La raíz La flor
El tallo El fruto
VEGETATIVOS REPRODUCTIVOS
Las hojas La semilla

Órgano Función
Raíz Fijación de la planta al suelo
Absorción de agua y minerales del suelo
En al gunas plantas son órganos de almacenami ento como en la
zanahoria y la yuca
Tallo Conecta la raíz y las hojas
Conduce agua y sales mineral es de la raíz a las hojas
Conduce sustancias elaboradas de las hojas a la raíz
En al gunas plantas son órganos de almacenami ento como en la
papa y la cebolla cabezona
Puede servir para la reproducción vegetativa de algunas
plantas.
Hoja Fotosíntesis o producción de alimento
Respiraci ón de la planta a través de estomas
Transpiración

Flor Formación de semillas

Reproducción sexual de la planta
Almacenamiento como en el brócoli, el colifl or
Fruto Guardar y proteger l as semillas
Almacenamiento de sustancias alimenticias
Semilla Contener el embri ón de l a nueva planta
Reservar sustancias alimenticias para el desarrollo y
crecimiento del embri ón

I. CLASIFICACIÓN ACTUAL DEL REINO VEGETAL:

REINO DE LAS PLANTAS

DIVISIÓN CLASES EJEMPLOS

Briofitas
(Plantas no vasculares) Hepaticópsida Marchantia
Carecen de tallos, hojas
y raíces verdaderas. Musgo
Mucópsida
Presentan rizoides. Polichitrum

Licofita Licopodio

Cola de
Sin semilla Esfenofita (Equisetos)
Traqueofitas Pteridofita caballo
o Cormofitas
(Plantas vasculares) Filicinófita Helecho
Tienen tejidos vasculares
diferenciados (xilema y Coniferofita o Gimnospermas: Las semillas son Pino, cedro
floema). desnudas y abeto
Antofitas o Angiospermas: Monocotiledóneas Maíz, trigo
Con semilla
Tienen flores, las semillas
Espermatofitas
están encerradas en el
ovario Dicotiledóneas Frijol, arveja

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Biología celular y molecular
 LA PARED CELULAR: Le da rigidez y resistencia a la planta y está compuesta de celulosa. El gran desa-
rrollo del sistema vascular relaciona el movimiento del agua en el interior con los movimientos citoplasmáticos
llamados ciclosis.
Algunas organelas son las mismas que se encuentran en las células animales como núcleo, mitocondrias,
retículo endoplasmático, aparato de Golgi (dictisomas), lisosomas, peroxisomas y citoesqueleto.
Otras son exclusivas de las células vegetales y determinan diferencias entre ellas y los tejidos animales
tanto a nivel estructural como funcional: vacuola hidrica, plastidios y glioxisomas.

CLOROPLASTOS: Evolutivamente descendientes de bacterias productoras de oxígeno. Se encuentran en

células vegetales y algas verdes y son los más grandes después de la vacuola, hay de 20 a 40 cloroplastos
en cada célula. Tiene dos membranas, un estroma con carbohidratos, lipidos proteínas ADN del cloroplasto
ARN, ribosomas, pigmentos fotosintéticos y unas estructuras llamadas tilacoides.
Debe su color verde al pigmento clorofila que absorbe las ondas de luz rojas y azules y refleja las ondas
verdes.

FOTOSÍNTESIS: Consiste en la elaboración de azúcares a partir de CO2 y la energía luminosa del sol que
las hojas toman directamente, además de agua y sales minerales que son absorbidos del suelo por las
raíces. Se divide en dos fases:

Fase luminosa; la luz que viene del sol a 680 y 700 nm producen la excitación del Mg contenido en la
molécula de clorofila provocando la ruptura de la molécula de agua y en ambos casos liberación de 5
electrones que pasan por una cadena transportadora de electrones que produce un gradiente electroquímico
de donde la ATPasa obtiene la energía para producir un ATP. La fotolisis del agua libera H2 que se unen al
NADP+ y oxígeno que se libera a la atmósfera.

Fase oscura; se lleva a cabo en el estroma de los cloroplastos, se utilizan el ATP y el NADPH2 formados
en la fase luminosa para fijar el CO2 que ha entrado por los estomas, produce con ella glucosa durante el
ciclo de Calvin Benson que luego será almacenada como almidón o empleada por la mitocondria.

II. MATERIALES:
A. EQUIPOS Y REACTIVOS
• Microscopio
• Lugol, azul de metileno, Safranina
• Aceite de cedro
• 1 hoja de bisturí
• Láminas portaobjetos y cubreobjetos.

B. MATERIAL BIOLÓGICO
• Catafilo de cebolla
• Cofia de raíz
• Corcho
• Hoja de helecho con sori
• Musgo
• Planta con hojas
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III. PROCEDIMIENTO
Proceder a montar cada una de las muestras biológicas solicitadas sobre la lámina portaobjeto previa
coloración con lugol o azul de metileno y safranina para su observación y descripción microscópica. Los
cortes transversales de las muestras deben ser lo más delgado posible a fin de facilitar la visibilidad y
detalles de las células de interés.

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Biología celular y molecular
IV. OBSERVACION
MUESTRA CARACTERÍSTICA DIBUJO

Experiencia de Robert Hooke

1 Corcho
observando restos de pared celular.

Observar las células embrionarias o

meristemáticas con núcleo grande,
2 Cofia de raíz
vacuola pequeña y pared celular
delgada.

Observar:
3 Catafilo de cebolla • Pared celular vegetal
• Núcleo

Observar:
• Núcleo y cloroplasto
• Epidermis, tricomas, estomas.
4 Mesofilo de hojas
• Células del parénquima
clorofiliano y parénquima
esponjoso.

Helechos y musgos. Se reproducen por

esporas.
5 Plantas Criptógamas Observar esporas y esporangios
contenidos en los sori del envés de los
helechos.

Tienen flores como estructura

reproductiva.
Producen semillas que germinan en el
suelo y que llevan el embrión.
6 Plantas Fanerógamas
Observar granos de polen contenidos
en las tecas del estambre y saco
embrionario al interior del rudimento
seminal en el ovario del pistilo.

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Biología celular y molecular
 TRABAJO DE INVESTIGACIÓN Nº 3

NIH Public Access

Author Manuscript
Nat Rev Drug Discov. Author manuscript; available in PMC 2010 April 12.
Published in final edited form as:
Nat Rev Drug Discov. 2008 March ; 7(3): 221–230. doi:10.1038/nrd2519.

Genome-wide association studies: progress and potential for drug

discovery and development
Stephen F. Kingsmore, Ingrid E. Lindquist, Joann Mudge, Damian D. Gessler, and William D. Beavis
National Center for Genome Resources, 2935 Rodeo Park Drive East, Santa Fe, New Mexico 87505, USA

Abstract

Although genetic studies have been critically important for the identification of therapeutic targets in
Mendelian disorders, genetic approaches aiming to identify targets for common, complex diseases
have traditionally had much more limited success. However, during the past year, a novel genetic
approach — genome-wide association (GWA) — has demonstrated its potential to identify common
genetic variants associated with complex diseases such as diabetes, inflammatory bowel disease
and cancer. Here, we highlight some of these recent successes, and discuss the potential for GWA
studies to identify novel therapeutic targets and genetic biomarkers that will be useful for drug
discovery, patient selection and stratification in common diseases.

Genetic factors are known to have an important role in many common diseases, and the identification
of genetic determinants for such diseases has the potential to provide insights into disease
pathogenesis, revealing novel therapeutic targets or strategies. Genetic factors could also provide
useful biomarkers for diagnosis, patient stratification and prognostic or therapeutic categorization.
In addition, given that inherited genetic factors are present at birth, knowledge of these factors could
facilitate timely preventative or ameliorative interventions.

During the past 25 years, genetic linkage-based studies have proved very effective in identifying
causal genetic factors in Mendelian (single gene) disorders; causal genes for more than 1,300
dominant and recessive Mendelian diseases have been identified1. Most common diseases and
endophenotypes, however, do not exhibit Mendelian inheritance, but rather feature complex,
multifactorial expression and inheritance. Although linkage-based methods have been broadly applied,
these studies have had little success in identifying the allelic determinants of common disorders2. In
particular, there has been poor replication among studies, whereby an initial study identifies an
allele (genotype) with large estimated genetic effects (relative risk) but subsequent studies fail to
corroborate the results3,4. In part, this reflects the dependence of linkage-based studies on unusually
informative families (with multiple affected and unaffected individuals), which induce a bias toward
rare, semi-Mendelian disease subsets in subpopulations. Reports of successful identification of
genetic variants in

Correspondence to S.F.K., [email protected].

DATABASES
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene APOE | ATG16L1 | BAT1 | C3 | CFB | CFH | CLEC16A | FTO
| GRM7 | HLA-B27 | HNF1B | IFIH1 | IL2RA | IL23R | NFKBIL1 | NOD2 | PTGER4 | PTPN2 | PTPN22 | RELA | TCF7L2 | WWC1
OMIM: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM age-related macular degeneration | acute myocardial infarction |
Alzheimer’s disease | anterior uveitis/ankylosing spondylitis | breast cancer | colorectal cancer | Crohn’s disease | prostate cancer |
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restless leg syndrome | type 1 diabetes mellitus | type 2 diabetes mellitus | ulcerative colitis
FURTHER INFORMATION
Stephen Kingsmore’s homepage: http://www.ncgr.org
ALL LINKS ARE ACTIVE IN THE ONLINE PDF

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Biología celular y molecular
 with discovery, replication and biological validation
common diseases using an approach that circumvents stages17 (FIG. 1). Tiered designs are critical for cost-
this limitation — genome-wide association (GWA) effective detection of meaningful, hypothesis-
studies — have therefore generated considerable generating, genotype– phenotype associations given
excitement. the large number of comparisons involved, prior
probability estimates of association, sample sizes,
Human GWA studies are based on three hypotheses: resampling procedures and statistical significance
First, the common trait/common variant hypothesis thresholds. GWA studies also owe their statistical
proposes that the genetic architecture of complex power to their large cohort size and high rate of SNP
traits consists of a limited number of common alleles, detection. Currently, a respected threshold for
each conferring a small increase in risk to the uncorrected, significant associations is P <5 × 10"7
individual5,6; second, the brief history of most human (REFS 18,19). Alleles with moderately less significant
populations precludes sufficient generations (or associations, however, are often also reported, as
meioses) to create recombination ev ents (or they might indicate loci that reach the aforementioned
mutations) between closely located, common threshold in subsequent studies.
(ancient) variants; and, third, suppression of meiotic
recombination (coldspots) occurs very frequently. Results of initial GWA studies
Thus, approximately 80% of the human genome is
The first GWA study, published in 2002, evaluated
comprised of around 10 kb regions that exhibit reduced
acute myocardial infarction (AMI)20. The discovery,
recombination in human populations (haplotypes)7.
or nomination, phase comprised the examination of
Genetic variants (alleles) within haplotypes are in
genotype–phenotype association signals in 65,671
linkage disequilibrium (LD). This phenomenon enables
coding domain SNPs (cSNPs) in 752 cases and
much of the recombination history in a population to
controls (TABLE 1). Although subsequent studies have
be ascertained by genotyping a large set of well- used up to 20 times this number of non-coding SNPs,
spaced, common (ancient) variants throughout the gene-tagging SNPs are more informative, as the
genome, especially if variant selection is informed by majority of true-positive associations are expected to
knowledge of haplotypes. During the last 10 years, be with genes1. Even more informative are screens
more than 10 million single nucleotide polymorphisms that empl oy f unctional cSNPs, such as
(SNPs) have been identified8. Furthermore, the nonsynonymous SNPs (nsSNPs), that are candidate,
International HapMap project has genotyped causal (risk-enhancing) gene alleles1,21–28. The
approximately 4 million common SNPs (occurring with replication, or confirmatory, phase examined
a minor-allele frequency of more than 5%) in human associations of 26 SNPs in 2,137 individuals and
populations and has assembled these genotypes confirmed association of AMI with a 50 kb region
computationally into a genome-wide map of SNP- containing lymphotoxin-á (LTA), nuclear factor of kappa
tagged haplotypes7. These resources, together with light polypeptide gene enhancer in B cells (also known
array technologies for massively parallel SNP as RELA), nuclear factor of kappa light polypeptide
genotyping and the well-established epidemiological gene enhancer in B cells inhibitor- like 1 (NFKBIL1)
case-control association studies have rendered GWA
and human leukocyte antigen (HLA)-B associated
feasible (BOX 1, FIG. 1). transcript 1 (BAT1) genes. Additional replication
Initial genetic association studies focused on studies have been undertaken, some of which have
candidate loci and exhibited a lack of replication confirmed an association of this region with AMI-
among studies9,10. There were biological explanations related phenotypes and, in particular, one nsSNP in
for inconsistent results: unobserved, confounding LTA29–35. The association of LTA with AMI was an
biological sources of heterogeneity, including unexpected finding, suggesting a novel therapeutic
inconsistent or poorly defined measurements of the target.
phenotype, heterogeneous genetic sources for the A second, pioneering GWA study examined age-
phenotype (genocopies), population stratification related macular degeneration (AMD)36 (TABLE 1). The
(et hnic ancestry), populat ion-speci f ic LD, discovery phase sought associations of 105,980
heterogeneous genetic and epigenetic backgrounds SNPs with AMD in 96 cases and 50 control individuals.
or het erogeneous env i ronmental inf luences Despite the small cohort size, SNPs in the
(phenocopies). In addition, there were statistical complement factor H (CFH) gene, including an nsSNP,
reasons for irreproducibility, including failure to control showed significant association with AMD. Replication
the rate of false discoveries, model misspecification was not performed, but subsequent studies have
and heterogeneous bias in estimated effects among replicated associations of CFH alleles with AMD37–
studies11–14. Also, a frequent source of non-replication 40. Of all common diseases examined by GWA to
was lack of power due to the limited number of date, AMD is unique in that a single haplotype explains
individuals genotyped and phenotyped15,16. 61% of the genetic variance, conferring a homozygous
In order to ameliorate poor replication, GW A odds ratio of 7.4. To put this in perspective, this is of
experiments employ multi-tiered experimental designs a similar magnitude to the classic associations of
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Biología celular y molecular
 great interest in alleles that exhibit pleiotropic
HLA- B27 with anterior uveitis/ankylosing spondylitis associations, as they potentially represent blockbuster
and HLA alleles with type 1 diabetes mellitus (T1DM). targets that cross- over therapeutic categories (TABLE
Complement pathway dysregulation was a novel, 2).
unexpected association with AMD. Subsequent
studies have shown an association of AMD with two In common with most GWA studies to date, estimated
additional members of the alternative complement genetic effects (relative risks) of IBD- associated loci
pathway (factor B (CFB) and C3)41,42. These findings, are small18,46. However, as many of these variants
together with biological validation studies, have led were common, the population attributable risk — an
to the initial development of new AMD therapies, based estimate of the percentage of cases of disease that
upon complement inhibition. would be avoided if the allele(s) were absent — was
substantial. Of several studies that looked for epistatic
In the past year, technical challenges associated with interactions between IBD association signals, two
GWA were largely overcome, genotyping costs were found suggestive evidence of epistasis involving two
decreased and a significant number of studies have different pairs of genes24,52.
used SNP genotyping arrays in larger population
groups to produce replicated associations between Diabetes mellitus
individual SNP alleles and common diseases.
A good example of the capabilities and limitations of
Inflammatory bowel disease GWA studies is type 2 diabetes mellitus18,53–57
Five large GWA studies have examined Crohn’s (T2DM; TABLE 1). Two studies examined association
disease and ulcerative colitis, two histologically both with SNPs and haplotypes in the discovery
distinct types of inflammatory bowel disease (IBD) phase54,57. Haplotype-based analysis can be more
(TABLE 1). Four of the studies used micro-arrays powerf ul than marker-by-marker analysis in
featuring between 300,000 and 400,000 SNPs18,43– association studies22,58–61. For example, haplotypes
45, whereas the fifth study genotyped approximately
can correlate a specific phenotype with a specific gene
16,000 nsSNPs24. Two follow-up studies sought to in a small population sample even when individual
replicate the most significant signals from the SNPs cannot 62. Case-control and family-based
Wellcome Trust case control consortium (WTCCC) association studies were employed in several studies
study18, one in a European population and another in of T2DM.
a Japanese population46,47. The European study
replicated significant signals of the WTCCC study, The replication phases of these studies were
but some of the alleles failed to reach significance in impressive; two of them included over 9,000 replication
the Japanese study and others were not detected. individuals53,54. One study sought to replicate signals
The failure to replicate signals in different studies might identified by the WTCCC study18 by genotyping the
ref lect true dif ferences between populations, most significant SNPs; 9 of 77 candidate SNPs
differences in phenotype ascertainment or a lack of reached a P <5 × 10"7 significance level63. The eight
power. genes represented by these SNPs were replicated in
at least one other independent study (TABLES 1–3).
Considering the six studies of European populations, The concordance of T2DM-associated genes between
there was significant replication of specific allele GWA studies is striking: of 10 novel associations,
associations with Crohn’s disease (TABLES 1,2). only two were unique to a single study.
Three associations were concordant in four out of five
studies (representing the genes caspase recruitment Reassuringly, some of the genes identified by GWA
domain 15 protein (CARD15, also known as NOD2), in studies of TD2M have previously been associated
interleukin 23 receptor (IIL23R) and ATG16 autophagy with the disease in other types of genetic studies. For
related 16-like 1 (ATG16L1)). Of note, CARD15 had example, transcription factor 7-like 2 (TCF7L2) had
previously been identified as a susceptibility gene by previously shown linkage to T2DM in the Icelandic
linkage-based approaches48 , 49 . O ne gene, population, and significant association in a candidate
prostaglandin E receptor 4 (PTGER4) showed gene association study 64 . Heterozygous and
association in two out of five studies. In addition, homozygous carriers of TCF7L2 risk alleles had
several disease-associated intergenic segments have relative risks of 1.45 and 2.41, respectively. TCF7L2
been replicated. IBD susceptibility genes that have is a transcription factor that regulates the pro-glucagon
been identified to date appear to coalesce into gene in entero-endocrine cells65. TCF7L2 alleles have
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biological networks involving innate immunity, also shown associations with endophenotypes such
autophagy and phagocytosis50. In addition, alleles of as a lower likelihood of response to the oral
two genes associated with Crohn’s disease (IL23R hypoglycaemic drug sulphonylurea66 and increased
and PTPN2) have shown association with other risk of progression to T2DM among persons with
autoimmune disorders21,51, suggesting the existence impaired glucose tolerance67.
of autoimmune susceptibility ‘supergenes’. There is
In common with IBD, T2DM associations exhibited
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Biología celular y molecular
small estimated-effect sizes. Some of the candidate T1DM, like rheumatoid arthritis and IBD, is an
genes from GWA studies were consistent with autoimmune disorder. Medical practitioners have long
biological processes that have previously been noted familial aggregation of autoimmune diseases.
implicated in the pathogenesis of T2DM, such as One study showed association of both rheumatoid
pancreatic islet beta-cell function and insulin arthritis and T1DM with specific polymorphisms
biosynthesis. However, these studies also suggested (IL2RA-rs2104286 and PTPN22-rs6679677; TABLE
new components of these processes, such as zinc 2)18. T1DM, rheumatoid arthritis and IBD also show
transport and Wnt-signalling56,64,68. Validation of association with MHC alleles74–76. These findings
T2DM candidate genes as therapeutic targets will suggest common underlying aetiological pathways
require additional studies to identif y causal (and therapeutic targets) for several, common
susceptibility alleles and to determine their precise autoimmune disorders77.
effect on cell biology.
Cancer
Three studies performed initial modelling of how loci
combine to affect susceptibility to T2DM56,63,69. One GWA studies of cancer based on common, inherited
study found evidence of epistatic interactions between SNPs are useful for the identification of germ-line risk
two genes. Otherwise, T2DM appeared to fit a alleles, but not somatic mutations. Three GWA studies
polygenic threshold model with additive/multiplicative sought inherited association signals in prostate
effects of individual loci. However, until the causal cancer53,78,79; FIG. 2 shows details of the discovery
alleles that underpin these association signals have phase of one of these studies. An association signal
been found, it is not possible to make categorical at chromosome 8q24 that had previously been
statements about the allelic architecture of T2DM. identified by linkage analysis80 was replicated in two
GWA studies53,79. In addition, these studies identified
Frequencies of T2DM associated alleles showed a second 8q24 association, approximately 300 kb
considerable variation between ethnic and racial upstream from the first. As yet, the functional basis
groups. Despite these differences, however, T2DM- of these associations is unclear. Although individual
associated risk alleles were conserved between 8q24 alleles showed modest estimated genetic
independent populations, implying an ancient origin effects, the cumulative effect of several loci fit a
of these polymorphisms70. multiplicative model that conferred a population-
attributable risk (PAR), that is, an expected reduction
Expansion of an initial association of an allele with a in prostate-cancer incidence if the risk alleles did not
categorical trait (such as the presence of a disease) exist in the population, of up to 68%81. As noted above,
wit h quantit ativ e com ponent phenotypes PAR values are strongly affected by allele frequency
(endophenotypes) is an approach pioneered with and represent only an approximate measure of the
apolipoprotein E (APOE) alleles in Alzheimer’s contribution of those alleles to disease incidence.
disease. It appears to be highly instructive in
elucidating the mechanism of action of alleles in One study of prostate cancer78 identified a TCF2 (also
disease pathogenesis. One T2DM GWA extended its known as HNF1B) susceptibility allele. Intriguingly,
analysis to a quantitative endophenotype: T2DM- this allele appeared to diminish the risk of T2DM
related obesity (measured by body-mass index (BMI); (TABLE 2), possibly representing antagonistic
TABLE 1)54,71. Alleles associated with T2DM in the pleiotropy. This is supported by epidemiological
fat-mass and obesity-associated gene (FTO)18,55,63 evidence which suggests that diabetic men have a
also showed an association with BMI (TABLES 2,3). slightly lower prostate cancer risk than non-diabetic
Association of FTO with obesity has since been men82.
confirmed72.
Another allele exhibiting association in two diseases
Two GWA studies examined T1DM. One examined is rs6983267 at chromosome 8q24, which has shown
6,500 nsSNPs28 and the other evaluated 392,575 replicated associations with prostate and colorectal
SNPs18. Four T1DM, susceptibility loci had previously cancer79,82–84 (TABLE 2).
been identified by linkage- based methods (class II
MHC alleles, CTLA4, PTPN22 and insulin). GWA Three GWA studies sought inherited associations with
studies replicated the association with PTPN22 and breast cancer19,85,86. Although each study identified
identified several novel loci, including C12orf30, significant novel loci, two genes and one allele were
KIAA0350 (also known as CLEC16A) and IFIH1 (each each supported in two studies.
replicated in two studies). Twenty-one T1DM
candidate genes that have previously shown linkage Complex traits
or association are currently undergoing replication In addition to common diseases, GWA studies are
studies73. applicable to complex traits. One study undertook
GWA with numerous quantitative and categorical

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Biología celular y molecular
 memory-associated endophenotypes87. Despite a effects of replicated associations have been uniformly
small discovery cohort (341 individuals), associations and surprisingly small.
with the KIBRA (also known as WWC1) gene have
been replicated87–89. A notable innovation in this study Encouragingly, most associated haplotype intervals
was that associations were sought with multi-scale identified to date are sufficiently small to feature a
and multi-modality endophenotypes; that is, single gene. In large measure, this reflects the use of
performance in seven memory-associated tests and several, outbred populations in confirmatory, fine-
f unctional magnetic resonance image-based mapping studies. Even when the association is within
measures of the hippocampus during three memory- a single gene, the predisposing variant might affect
associated tests. This study provides evidence that an adjacent gene, as in adult lactose intolerance99.
progress can be made in the elucidation of the genetic Although some association intervals have been found
determinants of subjective, qualitative neurologic traits to contain a single, unequivocally functional gene
by using obj ectiv e, quanti tativ e, surrogate variant, the causality of alleles has been established
endophenotypes. in only a minority of cases. Causal alleles identified
to date do not yet show much difference in genetic
As well as identifying novel associations, GWA studies mechanism from those identified in Mendelian
have confirmed several susceptibility genes that were disorders; this could reflect ascertainment bias1,83,84.
previously established by linkage analysis in large Many genes identified by GWA were not candidate
pedigrees. For example, a GWA study of late-onset genes previously, highlighting the hypothesis-
Alzheimer’s disease (LOAD) identified the well- informing value of genetic studies. Already, there are
established APOE- susceptibility allele90. This examples of potentially tractable therapeutic targets
association was also replicated in a study that that had not previously been considered in a disease
genotyped 17,343 putative functional cSNPs23. or trait. As yet, the confluence of associated genes
into biological networks and pathways is at an early
A remaining problem with large GWA studies is the
stage. In part, this reflects scant or incorrect annotation
cost of genotyping, but one study provided evidence
of many genes. There appears to be a significant
that sample pooling strategies might help to overcome
conservation of associations of common alleles
this issue. In a GWA study of bipolar disorder,
between human populations. Thus, to date, it appears
investigators created 39 pools, containing DNA from
that GWA studies are fulfilling expectations with regard
2,672 individuals91. These pools were used for both
discovery and replication experiments. Pools were to the elucidation of molecular mechanisms
individually genotyped for 555,235 SNPs and underpinning poorly understood, common diseases.
normalized allele frequencies were inferred from
In the few informative studies reported to date,
intensity data. Replicates were assayed for each pool.
endophenotypes have been highly instructive in
Thirty-sev en SNPs showing allele f requency
dissecting the network or pathway that is perturbed
differences in both cohorts were individually genotyped
by an individual allele, which affects a complex trait.
and one SNP retained a significant association. The
It is particularly exciting to see the application of multi-
aforementioned WTCCC study also studied bipolar
mode endophenotypes, such as combinations of
disorder, identifying an association at 16p12 (REF.
18). One locus, for glutamate receptor, metabotropic psychological testing, brain imaging and gene
expression87. This is clearly an area of potential
7 (GRM7), showed association in both studies.
opportunity.
The rate of publication of GWA studies continues to
increase. Recent studies have investigated asthma92, The cost of enrolling the very large cohorts that are
nicotine dependence93, coronary artery disease19,26, needed to discover and validate alleles with small effect
atrial fibrillation94, prolonged QT interval and sudden sizes has hitherto precluded the collection and
cardiac death95,96, coeliac disease97, lung cancer98, integration of rich, accurate clinical metadata. It is
psoriasis21 and liver cirrhosis25, among others (TABLE likely that future studies will use a much greater
1). stratification of traits than the phenotypically crude
studies reported so far. Recent GWA studies of breast
cancer provide a good example of the added genetic
Initial conclusions on the utility of GWA complexity that can be revealed by trait stratification19,
The utility of GWA studies for the identification of novel 85,86. In addition, following replication of associations
genomic associations with complex diseases has with categorical traits, it is anticipated that targeted
P9 BCyM upla.pmd

unambiguously been established over the past year. genotypic examination of many endophenotypes will
In general, GWA studies have employed large case– be highly instructive in the dissection of the role of
control cohorts featuring both familial and sporadic individual alleles in disease pathogenesis.
cases, categorical trait definitions and up to half a
million commonly polymorphic SNPs. To date, with GWA studies show significant potential to redefine
the exception of CFH in AMD, the estimated genetic disease classification. In some cases, GWA studies
9
Biología celular y molecular
are identifying molecular factors that enable patient example of this was the recent use of periodic limb
stratification and might prove useful in personalized movements and serum ferritin levels in GWA studies
medicine. Cancers provide the clearest examples of of restless leg syndrome100. An area of substantial
this to date. In other cases, exemplified by IBD, GWA future interest for the pharmaceutical industry will be
studies are poi nting to comm on mol ecul ar pharmacogenetic GWA studies to identify markers
underpinnings in diseases that were believed to be for patient stratification in clinical trials. Comprehensive
distinct. In restless leg syndrome, replicated pharmacogenetic information will, in turn, facilitate the
associations have provided concrete evidence that the practice of personalized medicine. Pharmacogenetic
phenotype represents a bona fide neurological GWA studies and early adoption of personalized
disorder100,101. In mental illness, there is great therapy are likely to be used in the selection of
anticipation that GWA studies will provide an objective, expensive or chronic medications in life threatening
molecular revision of disease categorization. conditions or where the therapeutic index is narrow or
adverse event concerns are high, such as cancer
Many questions remain concerning the genetic chemotherapy.
architecture of common diseases. These include the
extent of locus and allelic heterogeneity, fit with an Despite the current excitement, GWA studies have
additive-threshold model or, alternatively, the extent only been able to account for a small proportion of
of epistasis (the relative contributions of rare and the expected genetic variance in complex traits24,102.
common, and high and low, penetrance alleles) and This is not surprising given current limitations. First,
v arious types of v ariation, f rom genome current GWA studies are designed to identify common
rearrangements to SNPs. GWA studies are not risk alleles that are predicted to be important in
designed to evaluate these questions. Once loci have complex disorders under the common disease/
been identified, however, methods such as deep common alleles hypothesis5,6. Increasing evidence
resequencing can nominate candidate susceptibility suggests that some complex disorders and traits, such
alleles and provide data for the evaluation of genetic as schizophrenia, hypercholesterolaemia and body
architecture 102 . Meaningf ul, indi v idual risk mass, are genetically heterogeneous104–
determinations will require the identification of causal 107. e genetic basis of such diseases is more likely
alleles, the development of multiplexed molecular to conform to the common trait/rare variant hypothesis,
diagnostics and significant modelling. which proposes that many rare variants exist, with
substant ial allel ic heterogenei ty at causal
Future developments and implications loci58,108,109. The GWA approach is unable to detect
The trends observed in recent GWA studies are susceptibility loci that harbour numerous, individually
rare (recent), polymorphisms. Instead, a resequencing
anticipated to continue. Chips with 900,000 and
approach will be needed to identify rare alleles.
1,000,000 million SNPs were recently launched and
Encouragingly, massively parallel sequencing
genotyping accuracies have improved. Cohort sizes
methods provide a potential solution102, 107, 110,
are steadily increasing and biobanks of unparalleled
suggesting disease-specific rare alleles and recent
size and phenotype definition are being established.
mutations that provide supplementary genotyping
Combinations of genotype- and haplotype-based array content. Second, a proportion of the genome
associations are becoming more prev alent. cannot effectively be examined on the basis of tag
Experimental designs and statistical methods are also SNP genotypes. Approximately 20% of the genome
becoming more uniform, enabling more meaningful is comprised of recombination hotspots that are not
meta-analysis. In particular, the emergence of adaptive amenable to LD-based approaches7. Alternatively, at
designs and the use of Bayesian inferential methods recombination coldspots, haplotype blocks might be
will produce a probabilistic synthesis from combined too large for unambiguous identification of causal loci.
analyses83. Importantly, this will provide an intuitive The extent of the effect of genomic copy number
framework for combining information from multiple variation (CNV) on association signals is not yet clear,
studies, resulting in more effective detection and although recent genotyping arrays do provide CNV
replication of weak associations103. information. Insufficient numbers of cases will be
available for GWA studies of many orphan diseases,
As noted above, phenotypes studied to date have
uncommon disease complications or adverse events.
been crude. The use of endophenotypes is expected
For some common diseases, these considerations
to increase significantly. In particular, biomarker
could obfuscate a substantial proportion of the genetic
phenotypes are anticipated to become widely used.
variance. Supplementation of genotyping array content
These will probably include gene expression,
reflective of CNV regions should, however, circumvent
proteomic, metabolomic and imaging biomarkers. As
some of these limitations. Use of adaptive statistical
determinants of complex traits are identified, genetic
methods and resampling strategies might also
stratification will become possible, potentially reducing
circumvent the need for thousands of affected
the genetic complexity of traits and enabling the
individuals in studies of orphan diseases83.
identification of additional association signals. An

10
Biología celular y molecular
 GWA successes are creating substantial need for Glossary
downstream genetics, biochemistry and cell biology
efforts to confirm the biological relevance of genotype– Gen etic lin kage Co-segregati on (reduced
phenotype associations and to elucidate the recombination) of a trait and an allele in related
underlying mechanisms of disease. This is especially subjects (pedigrees) more often than explicable
true of association signals in gene deserts or alleles by chance
without apparent functional consequence. Translation Dominant An allele that confers a trait even when it
of the fruits of GWA studies to clinical practice will is heterozygous (present as a single copy in a
require the derivation of predictive models of the genetic genome)
architecture of complex traits that evaluate with much Recessive An allele that confers a trait only when it
greater precision the contributions of factors such as is homozygous (present in two copies in a
epistasis, genocopies, phenocopies and penetrance. genome, one from each parent)
Endophenotype A measurable component of a
phenotype
Box 1 Multifactorial Inheritance of a trait that is attributable
to two or more genes and their interaction with
Useful resources and databases for genetic-based
the environment (also known as polygenic
studies
inheritance)
• Genetic Association Database: An archive of
Allele The DNA code at a given locus (position) on a
human genetic association studies of complex
chromosome
diseases. http://geneticassociationdb.nih.gov/
• Schizophrenia Gene Database: An archive of Genome-wide association study A comprehensive
genetic association studies performed on search of the human genome for genetic risk
schizophreni a phenotypes. http:// factors for a trait by a case-control association
www.schizophreniaf orum.org/res/sczgene/ study involving comparisons of hundreds of
default.asp thousands of alleles between unrelated subjects
• Online Mendelian Inheritance in Man: A catalogue with and without a trait
of human genes and genetic disorders. http:// Haplotype A combination of alleles at linked loci (on
www. nc bi . nl m .ni h. gov / si t es/ a single chromatid) that are transmitted together
entrez?db=OMIM&itool=toolbar more often than explicable by chance
• Human Gene Mutation Database. A catalogue of Linkage disequilibrium (LD). Combinations of
published gene lesions responsible for human
alleles in a population that differ in frequency from
inherited disease. http://www.hgmd.cf.ac.uk/ac/
that expected f rom random f ormation of
index.php
haplotypes from alleles based on their frequencies
• Human Genome Variation Database: A catalogue
of normal human gene and genome variation. Minor-allele frequency The allele frequency of the
http://www.hgvbase.org/ less frequently occurring allele of a polymorphism
• dbSNP: A catalogue of human single nucleotide Case–control association study Comparison of the
polymorphisms. http://www.ncbi.nlm.nih.gov/ frequency of an allele between unrelated subjects
projects/SNP/ with and without a trait. A difference in allele
frequency between the two groups indicates that
• GeneSNPs: A database of polymorphisms in the allele might change the likelihood of the trait
human genes that are thought to have a role in Genetic association Correlation of a trait and an
susceptibility to environmental exposure. http:// allele in a population more often than explicable
www.genome.utah.edu/genesnps/
by chance
• PharmGKB: A database of pharmacogenomics
Genocopy A genotype at a locus that produces a
research. http://www.pharmgkb.org/index.jsp
phenotype that is indistinguishable from that
• GeneCards: A database of human genes that
produced by a genotype at another locus
includes genomic, proteomic and transcriptomic
Phenocopy An environmentally produced phenotype
information, as well as orthologies, disease
relationships, SNPs, gene expression and gene that simulates the effect of a particular genotype
function. http://www.genecards.org/ Non-synonymous SNP (nsSNP). A SNP that leads
to a change in the amino-acid sequence of the
P9 BCyM upla.pmd

Acknowledgments gene’s resulting protein and that might therefore

A Deo lumen, ab amicis auxilium. This work was partially affect its function
supported by National Institutes of Health grants N01A000,064 Odds rati A measure of risk that compares the
and U01AI066,569, and by National Science Foundation grant probability of occurrence of a disease in a group
0524,775. The authors thank the reviewers for their helpful
suggestions.
with a risk allele with the probability in a control
group
11
Biología celular y molecular
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P9 BCyM upla.pmd

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Biología celular y molecular