title: Systematic identification of trans eQTLs as putative drivers of known disease associations.
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.
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands.
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Westra
authors.affiliation: 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.
authors.forename: Marjolein J
authors.initials: MJ
authors.lastname: Peters
authors.affiliation: Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, Exeter, EX1 2LU, UK.
authors.forename: Hanieh
authors.initials: H
authors.lastname: Yaghootkar
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17487 Greifswald, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schurmann
authors.affiliation: Institute for Molecular Medicine Finland FIMM, FI-00014 University of Helsinki, Helsinki, Finland.|Department of Chronic Disease Prevention, National Institute for Health and Welfare, FI-00271 Helsinki, Finland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kettunen
authors.affiliation: Cardiovascular Health Research Unit, University of Washington, Seattle, WA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Christiansen
authors.affiliation: Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.|Department of Oncology, Cancer and Haematology Centre, Churchill Hospital, Oxford, OX3 7LJ.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fairfax
authors.affiliation: Institute of Human Genetics, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Human Genetics, Technical University Munich, Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schramm
authors.affiliation: University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.|The Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Powell
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands.
authors.forename: Daria V
authors.initials: DV
authors.lastname: Zhernakova
authors.affiliation: Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.affiliation: Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Van den Berg
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands.
authors.forename: Juha
authors.initials: J
authors.lastname: Karjalainen
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands.
authors.forename: Sebo
authors.initials: S
authors.lastname: Withoff
authors.affiliation: 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 Epidemiology, Erasmus Medical Center Rotterdam, the Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, the Netherlands.|Department of Epidemiology, Erasmus Medical Center Rotterdam, the Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: 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 Epidemiology, Erasmus Medical Center Rotterdam, the Netherlands.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Peter A C 't
authors.initials: PAC'
authors.lastname: Hoen
authors.affiliation: Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.
authors.forename: Eva
authors.initials: E
authors.lastname: Reinmaa
authors.affiliation: Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.
authors.forename: Krista
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.
authors.forename: Mari
authors.initials: M
authors.lastname: Nelis
authors.affiliation: Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.
authors.forename: Lili
authors.initials: L
authors.lastname: Milani
authors.affiliation: Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Barrack Road, Exeter, EX2 5DW, UK.
authors.forename: David
authors.initials: D
authors.lastname: Melzer
authors.affiliation: Clinical Research Branch, National Institute on Aging NIA-ASTRA Unit, Harbor Hospital, MD, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD, USA.|Department of Molecular Neuroscience and Reta Lila Laboratories, Institute of Neurology, UCL, Queen Square House, Queen Square, London WC1N 3BG, UK.
authors.forename: Dena G
authors.initials: DG
authors.lastname: Hernandez
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17487 Greifswald, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nauck
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, D-17487 Greifswald, Germany.
authors.forename: Dörte
authors.initials: D
authors.lastname: Radke
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17487 Greifswald, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.affiliation: 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.
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.affiliation: Department of Chronic Disease Prevention, National Institute for Health and Welfare, FI-00271 Helsinki, Finland.
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.affiliation: Cardiovascular Health Research Unit, University of Washington, Seattle, WA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brody
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, WA, USA.
authors.forename: Astrid
authors.initials: A
authors.lastname: Suchy-Dicey
authors.affiliation: Computational Medicine Core, Center for Lung Biology, Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Sina A
authors.initials: SA
authors.lastname: Gharib
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, WA, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Enquobahrie
authors.affiliation: Department of Statistics, University of Auckland, Auckland, New Zealand.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lumley
authors.affiliation: Queensland Institute of Medical Research, Herston, Brisbane, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Seiko
authors.initials: S
authors.lastname: Makino
authors.affiliation: Institute of Human Genetics, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Human Genetics, Technical University Munich, Munich, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, University Düsseldorf, Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Herder
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, University Düsseldorf, Düsseldorf, Germany.|Departments of Endocrinology & Diabetology & Metabolic Diseases, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.affiliation: Institute of Human Genetics, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Human Genetics, Technical University Munich, Munich, Germany.|German Center for Cardiovascular Research (DZHK), Germany; Munich Heart Allience, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Neuherberg, Germany.|Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: Groningen Bioinformatics Centre, University of Groningen, Groningen, the Netherlands.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Groningen Bioinformatics Centre, University of Groningen, Groningen, the Netherlands.
authors.forename: Ritsert C
authors.initials: RC
authors.lastname: Jansen
authors.affiliation: University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.|The Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
authors.affiliation: Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Knight
authors.affiliation: Cardiovascular Health Research Unit, University of Washington, Seattle, WA.|Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.affiliation: Institute for Molecular Medicine Finland FIMM, FI-00014 University of Helsinki, Helsinki, Finland.|Department of Chronic Disease Prevention, National Institute for Health and Welfare, FI-00271 Helsinki, Finland.|Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus,CB10 1SA, Hinxton, UK.
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17487 Greifswald, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, Exeter, EX1 2LU, UK.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.affiliation: Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: 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.
authors.forename: Joyce B J
authors.initials: JBJ
authors.lastname: van Meurs
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
mesh_terms: D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci