Systematic identification of trans eQTLs as putative drivers of known disease associations

Harm-Jan Westra(University Medical Center Groningen), Marjolein J. Peters(Netherlands Consortium for Healthy Ageing), Tōnu Esko(University of Tartu), Hanieh Yaghootkar(University of Exeter), Claudia Schurmann(Universitätsmedizin Greifswald), Johannes Kettunen(University of Helsinki), Mark Christiansen(University of Washington), Benjamin P. Fairfax(Centre for Human Genetics), Katharina Schramm(Helmholtz Zentrum München), Joseph E. Powell(The University of Queensland), Alexandra Zhernakova(University Medical Center Groningen), Daria V. Zhernakova(University Medical Center Groningen), Jan H. Veldink(University Medical Center Utrecht), Leonard H. van den Berg(University Medical Center Utrecht), Juha Karjalainen(University Medical Center Groningen), Sebo Withoff(University Medical Center Groningen), André G. Uitterlinden(Erasmus MC), Albert Hofman(Erasmus MC), Fernando Rivadeneira(Erasmus MC), Peter A.C. ’t Hoen(Leiden University Medical Center), Eva Reinmaa(University of Tartu), Krista Fischer(University of Tartu), Mari Nelis(University of Tartu), Lili Milani(University of Tartu), David Melzer(University of Exeter), Luigi Ferrucci(National Institute on Aging), Andrew Singleton(National Institutes of Health), Dena Hernández(National Institutes of Health), Michael A. Nalls(National Institutes of Health), Georg Homuth(Universitätsmedizin Greifswald), Matthias Nauck(Universitätsmedizin Greifswald), Dörte Radke(Universitätsmedizin Greifswald), Uwe Völker(Universitätsmedizin Greifswald), Markus Perola(Finnish Institute for Health and Welfare), Veikko Salomaa(Finnish Institute for Health and Welfare), Jennifer A. Brody(University of Washington), Astrid M. Suchy‐Dicey(University of Washington), Sina A. Gharib(University of Washington), Daniel A. Enquobahrie(University of Washington), Thomas Lumley(University of Auckland), Grant W. Montgomery(QIMR Berghofer Medical Research Institute), Seiko Makino(Centre for Human Genetics), Holger Prokisch(Helmholtz Zentrum München), Christian Herder(Deutsches Diabetes-Zentrum e.V.), Michael Roden(Düsseldorf University Hospital), Harald Grallert(Helmholtz Zentrum München), Thomas Meitinger(Helmholtz Zentrum München), Konstantin Strauch(Helmholtz Zentrum München), Yang Li(University of Groningen), Ritsert C. Jansen(University of Groningen), Peter M. Visscher(The University of Queensland), Julian C. Knight(Centre for Human Genetics), Bruce M. Psaty(Group Health Cooperative), Samuli Ripatti(Wellcome Sanger Institute), Alexander Teumer(Universitätsmedizin Greifswald), Timothy M. Frayling(University of Exeter), Andres Metspalu(University of Tartu), Joyce B. J. van Meurs(Netherlands Consortium for Healthy Ageing), Lude Franke(University Medical Center Groningen)
Nature Genetics
September 8, 2013
10.1038/ng.2756
Cited by 1,767Open Access
Full Text

Abstract

Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3' UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.

Related Papers

Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes
Jeffrey C. Barrett, David Clayton, Patrick Concannon et al.|Nature Genetics|2009|1.8k
Trait-Associated SNPs Are More Likely to Be eQTLs: Annotation to Enhance Discovery from GWAS
Dan L. Nicolae, Eric R. Gamazon, Wei Zhang et al.|PLoS Genetics|2010|1.4k
Understanding mechanisms underlying human gene expression variation with RNA sequencing
Joseph K. Pickrell, John C. Marioni, Athma A. Pai et al.|Nature|2010|1.4k
Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus
Jianwen Han, Hou‐Feng Zheng, Yong Cui et al.|Nature Genetics|2009|943
Mapping cis- and trans-regulatory effects across multiple tissues in twins
Elin Grundberg, Kerrin S. Small, Åsa K. Hedman et al.|Nature Genetics|2012|785