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

Authors: Harm-Jan Westra|||Marjolein J Peters|||Tõnu Esko|||Hanieh Yaghootkar|||Claudia Schurmann|||Johannes Kettunen|||Mark W Christiansen|||Benjamin P Fairfax|||Katharina Schramm|||Joseph E Powell|||Alexandra Zhernakova|||Daria V Zhernakova|||Jan H Veldink|||Leonard H Van den Berg|||Juha Karjalainen|||Sebo Withoff|||André G Uitterlinden|||Albert Hofman|||Fernando Rivadeneira|||Peter A C 't Hoen|||Eva Reinmaa|||Krista Fischer|||Mari Nelis|||Lili Milani|||David Melzer|||Luigi Ferrucci|||Andrew B Singleton|||Dena G Hernandez|||Michael A Nalls|||Georg Homuth|||Matthias Nauck|||Dörte Radke|||Uwe Völker|||Markus Perola|||Veikko Salomaa|||Jennifer Brody|||Astrid Suchy-Dicey|||Sina A Gharib|||Daniel A Enquobahrie|||Thomas Lumley|||Grant W Montgomery|||Seiko Makino|||Holger Prokisch|||Christian Herder|||Michael Roden|||Harald Grallert|||Thomas Meitinger|||Konstantin Strauch|||Yang Li|||Ritsert C Jansen|||Peter M Visscher|||Julian C Knight|||Bruce M Psaty|||Samuli Ripatti|||Alexander Teumer|||Timothy M Frayling|||Andres Metspalu|||Joyce B J van Meurs|||Lude Franke

Journal: Nature genetics

Publication Type: Journal Article

Date: 2013

DOI: NIHMS571772

ID: 24013639

Affiliations:

Affiliations

    Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands.|||Department of Internal Medicine, Erasmus Medical Centre Rotterdam, the Netherlands.|||Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.|||Genetics of Complex Traits, University of Exeter Medical School, Exeter, EX1 2LU, UK.|||Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17487 Greifswald, Germany.|||Institute for Molecular Medicine Finland FIMM, FI-00014 University of Helsinki, Helsinki, Finland.|||Cardiovascular Health Research Unit, University of Washington, Seattle, WA.|||Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.|||Institute of Human Genetics, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|||University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.|||Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands.|||Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands.|||Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, the Netherlands.|||Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, the Netherlands.|||Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands.|||Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands.|||Department of Internal Medicine, Erasmus Medical Centre Rotterdam, the Netherlands.|||The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, the Netherlands.|||Department of Internal Medicine, Erasmus Medical Centre Rotterdam, the Netherlands.|||Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.|||Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.|||Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.|||Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.|||Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.|||Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Barrack Road, Exeter, EX2 5DW, UK.|||Clinical Research Branch, National Institute on Aging NIA-ASTRA Unit, Harbor Hospital, MD, USA.|||Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD, USA.|||Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD, USA.|||Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD, USA.|||Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17487 Greifswald, Germany.|||Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany.|||Institute for Community Medicine, University Medicine Greifswald, D-17487 Greifswald, Germany.|||Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17487 Greifswald, Germany.|||Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.|||Department of Chronic Disease Prevention, National Institute for Health and Welfare, FI-00271 Helsinki, Finland.|||Cardiovascular Health Research Unit, University of Washington, Seattle, WA.|||Department of Epidemiology, University of Washington, Seattle, WA, USA.|||Computational Medicine Core, Center for Lung Biology, Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.|||Department of Epidemiology, University of Washington, Seattle, WA, USA.|||Department of Statistics, University of Auckland, Auckland, New Zealand.|||Queensland Institute of Medical Research, Herston, Brisbane, Australia.|||Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.|||Institute of Human Genetics, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|||Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, University Düsseldorf, Düsseldorf, Germany.|||Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, University Düsseldorf, Düsseldorf, Germany.|||Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|||Institute of Human Genetics, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|||Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Neuherberg, Germany.|||Groningen Bioinformatics Centre, University of Groningen, Groningen, the Netherlands.|||Groningen Bioinformatics Centre, University of Groningen, Groningen, the Netherlands.|||University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.|||Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.|||Cardiovascular Health Research Unit, University of Washington, Seattle, WA.|||Institute for Molecular Medicine Finland FIMM, FI-00014 University of Helsinki, Helsinki, Finland.|||Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17487 Greifswald, Germany.|||Genetics of Complex Traits, University of Exeter Medical School, Exeter, EX1 2LU, UK.|||Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.|||Department of Internal Medicine, Erasmus Medical Centre Rotterdam, the Netherlands.|||Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands.

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.

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