Trait-Associated SNPs Are More Likely to Be eQTLs: Annotation to Enhance Discovery from GWAS

English version České info

Although genome-wide association studies (GWAS) of complex traits have yielded more reproducible associations than had been discovered using any other approach, the loci characterized to date do not account for much of the heritability to such traits and, in general, have not led to improved understanding of the biology underlying complex phenotypes. Using a web site we developed to serve results of expression quantitative trait locus (eQTL) studies in lymphoblastoid cell lines from HapMap samples (http://www.scandb.org), we show that single nucleotide polymorphisms (SNPs) associated with complex traits (from http://www.genome.gov/gwastudies/) are significantly more likely to be eQTLs than minor-allele-frequency–matched SNPs chosen from high-throughput GWAS platforms. These findings are robust across a range of thresholds for establishing eQTLs (p-values from 10⁻⁴–10⁻⁸), and a broad spectrum of human complex traits. Analyses of GWAS data from the Wellcome Trust studies confirm that annotating SNPs with a score reflecting the strength of the evidence that the SNP is an eQTL can improve the ability to discover true associations and clarify the nature of the mechanism driving the associations. Our results showing that trait-associated SNPs are more likely to be eQTLs and that application of this information can enhance discovery of trait-associated SNPs for complex phenotypes raise the possibility that we can utilize this information both to increase the heritability explained by identifiable genetic factors and to gain a better understanding of the biology underlying complex traits.

Vyšlo v časopise: Trait-Associated SNPs Are More Likely to Be eQTLs: Annotation to Enhance Discovery from GWAS. PLoS Genet 6(4): e32767. doi:10.1371/journal.pgen.1000888
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000888

Souhrn

Zdroje

1. ColemanHR

ChanCC

FerrisFL3rd

ChewEY

2008 Age-related macular degeneration. Lancet 372 1835 1845

2. BarrettJC

HansoulS

NicolaeDL

ChoJH

DuerrRH

2008 Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40 955 962

3. KlionskyDJ

2009 Crohn's disease, autophagy, and the Paneth cell. N Engl J Med 360 1785 1786

4. HampeJ

FrankeA

RosenstielP

TillA

TeuberM

2007 A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 39 207 211

5. ManolioTA

CollinsFS

CoxNJ

GoldsteinDB

HindorffLA

2009 Finding the missing heritability of complex diseases. Nature 461 747 753

6. GoldsteinDB

2009 Common genetic variation and human traits. N Engl J Med 360 1696 1698

7. HirschhornJN

2009 Genomewide association studies–illuminating biologic pathways. N Engl J Med 360 1699 1701

8. KraftP

HunterDJ

2009 Genetic risk prediction–are we there yet? N Engl J Med 360 1701 1703

9. GamazonER

ZhangW

KonkashbaevA

DuanS

KistnerEO

SCAN: SNP and copy number annotation. Bioinformatics 26 259 262

10. HindorffLA

JunkinsHA

MehtaJP

ManolioAT

2009 A Catalog of Published Genome-Wide Association Studies

11. WTCCC 2007 Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 661 678

12. SchadtEE

LambJ

YangX

ZhuJ

EdwardsS

2005 An integrative genomics approach to infer causal associations between gene expression and disease. Nat Genet 37 710 717

13. SchadtEE

MolonyC

ChudinE

HaoK

YangX

2008 Mapping the genetic architecture of gene expression in human liver. PLoS Biol 6 e107 doi:10.1371/journal.pbio.0060107

14. SchadtEE

2009 Molecular networks as sensors and drivers of common human diseases. Nature 461 218 223

15. EmilssonV

ThorleifssonG

ZhangB

LeonardsonAS

ZinkF

2008 Genetics of gene expression and its effect on disease. Nature 452 423 428

16. HindorffLA

SethupathyP

JunkinsHA

RamosEM

MehtaJP

2009 Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A 106 9362 9367

17. LevyD

EhretGB

RiceK

VerwoertGC

LaunerLJ

2009 Genome-wide association study of blood pressure and hypertension. Nat Genet

18. ComabellaM

CraigDW

Camina-TatoM

MorcilloC

LopezC

2008 Identification of a novel risk locus for multiple sclerosis at 13q31.3 by a pooled genome-wide scan of 500,000 single nucleotide polymorphisms. PLoS ONE 3 e3490 doi:10.1371/journal.pone.0003490

19. HovattaI

ZapalaMA

BroideRS

SchadtEE

LibigerO

2007 DNA variation and brain region-specific expression profiles exhibit different relationships between inbred mouse strains: implications for eQTL mapping studies. Genome Biol 8 R25

20. GerritsA

LiY

TessonBM

BystrykhLV

WeersingE

2009 Expression quantitative trait loci are highly sensitive to cellular differentiation state. PLoS Genet 5 e1000692 doi:10.1371/journal.pgen.1000692

21. CowleyMJ

CotsapasCJ

WilliamsRB

ChanEK

PulversJN

2009 Intra- and inter-individual genetic differences in gene expression. Mamm Genome 20 281 295

22. DimasAS

DeutschS

StrangerBE

MontgomerySB

BorelC

2009 Common Regulatory Variation Impacts Gene Expression in a Cell Type-Dependent Manner. Science

23. BullaugheyK

ChavarriaC

CoopG

GiladY

2009 Expression Quantitative Trait Loci detected in cell-lines are often present in primary tissues. Hum Molec Genet in press

24. ChoyE

YelenskyR

BonakdarS

PlengeRM

SaxenaR

2008 Genetic analysis of human traits in vitro: drug response and gene expression in lymphoblastoid cell lines. PLoS Genet 4 e1000287 doi:10.1371/journal.pgen.1000287

25. IrizarryRA

WarrenD

SpencerF

KimIF

BiswalS

2005 Multiple-laboratory comparison of microarray platforms. Nat Methods 2 345 350

26. ShiL

ReidLH

JonesWD

ShippyR

WarringtonJA

2006 The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements. Nat Biotechnol 24 1151 1161

27. StarkAL

ZhangW

MiS

DuanS

O'DonnellPH

Heritable and non-genetic factors as variables of pharmacologic phenotypes in lymphoblastoid cell lines. Pharmacogenomics J

28. NicolaeDL

2006 Quantifying the amount of missing information in genetic association studies. Genet Epidemiol 30 703 717

29. DuanS

HuangRS

ZhangW

BleibelWK