Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis

Urmo Võsa(University Medical Center Groningen), Annique Claringbould(University Medical Center Groningen), Harm-Jan Westra(University Medical Center Groningen), Marc Jan Bonder(University Medical Center Groningen), Patrick Deelen(University Medical Center Groningen), Biao Zeng(Georgia Institute of Technology), Holger Kirsten(Leipzig University), Ashis Saha(Johns Hopkins University), Roman Kreuzhuber(European Bioinformatics Institute), Silva Kasela(University of Tartu), Natalia Pervjakova(University of Tartu), Isabel Alvaes(Ontario Institute for Cancer Research), Marie-Julie Favé(Ontario Institute for Cancer Research), Mawussé Agbessi(Ontario Institute for Cancer Research), Mark Christiansen(University of Washington), Rick Jansen(Vrije Universiteit Amsterdam), Ilkka Seppälä(Tampere University), Tong Lin(Chicago Department of Public Health), Alexander Teumer(Institute for Community Health), Katharina Schramm(Center for Environmental Health), Gibran Hemani(University of Bristol), Joost Verlouw(Erasmus University Rotterdam), Hanieh Yaghootkar(University of Exeter), Reyhan Sönmez(SIB Swiss Institute of Bioinformatics), Andrew Brown(University of Geneva), Viktorija Kukushkina(University of Tartu), Anette Kalnapenkis(University of Tartu), Sina Rüeger(University of Lausanne), Eleonora Porcu(University of Lausanne), Jaanika Kronberg-Guzman(University of Tartu), Johannes Kettunen(University of Helsinki), Joseph E. Powell(Garvan Institute of Medical Research), Bernett Lee(Agency for Science, Technology and Research), Futao Zhang(The University of Queensland), Wibowo Arindrarto(Leiden University Medical Center), Frank Beutner(Leipzig Heart Institute), Harm Brugge(University Medical Center Groningen), Julia Dmitreva(University of Liège), Mahmoud Elansary(University of Liège), Benjamin P. Fairfax(Centre for Human Genetics), Michel Georges(University of Liège), Bastiaan T. Heijmans(Leiden University Medical Center), Mika Kähönen(Tampere University), Yungil Kim(Johns Hopkins University), Julian C. Knight(Centre for Human Genetics), Péter Kovács(IFB Adiposity Diseases), Knut Krohn(Center for Clinical Research (United States)), Shuang� Li(University Medical Center Groningen), Markus Loeffler(Leipzig University), Urko M. Marigorta(Georgia Institute of Technology), Hailang Mei(Leiden University Medical Center), Yukihide Momozawa(University of Liège), Martina Müller‐Nurasyid(Center for Environmental Health), Matthias Nauck(Universitätsmedizin Greifswald), Michel G. Nivard(Vrije Universiteit Amsterdam), Brenda W.J.H. Penninx(Vrije Universiteit Amsterdam), Jonathan K. Pritchard(Stanford University), Olli T. Raitakari(University of Turku), Olaf Rotzchke(Agency for Science, Technology and Research), P. Eline Slagboom(Leiden University Medical Center), Coen D.A. Stehouwer(Maastricht University Medical Centre), Michael Stümvoll(Leipzig University), Patrick Sullivan(Karolinska Institutet), Peter A.C. ’t Hoen(Radboud University Nijmegen), Joachim Thiery(Life University), Anke Tönjes(Leipzig University), Jenny van Dongen(Vrije Universiteit Amsterdam), Maarten van Iterson(Leiden University Medical Center), Jan H. Veldink(University Medical Center Utrecht), Uwe Völker(Universitätsmedizin Greifswald), Cisca Wijmenga(University Medical Center Groningen), Morris A. Swertz(Genomics (United Kingdom)), Anand Kumar Andiappan(Agency for Science, Technology and Research), Grant W. Montgomery(The University of Queensland), Samuli Ripatti(University of Helsinki), Markus Perola(University of Helsinki), Zoltán Kutalik(University of Lausanne), Emmanouil T. Dermitzakis(University of Geneva), Sven Bergmann(SIB Swiss Institute of Bioinformatics), Timothy M. Frayling(University of Exeter), Joyce B. J. van Meurs(Erasmus University Rotterdam), Holger Prokisch(Helmholtz Zentrum München), Habibul Ahsan(Chicago Department of Public Health), Brandon L. Pierce(Chicago Department of Public Health), Terho Lehtimäki(Tampere University), Dorret I. Boomsma(Vrije Universiteit Amsterdam), Bruce M. Psaty(Kaiser Permanente Washington Health Research Institute), Sina A. Gharib(University of Washington), Philip Awadalla(Ontario Institute for Cancer Research), Lili Milani(University of Tartu), Willem H. Ouwehand(NHS Blood and Transplant), Kate Downes(NHS Blood and Transplant), Oliver Stegle(European Bioinformatics Institute), Alexis Battle(Johns Hopkins University), Jian Yang(The University of Queensland), Peter M. Visscher(The University of Queensland), Markus Scholz(Leipzig University), Gregory Gibson(Georgia Institute of Technology), Tõnu Esko(University of Tartu), Lude Franke(University Medical Center Groningen)
bioRxiv (Cold Spring Harbor Laboratory)
October 19, 2018
10.1101/447367
Cited by 545Open Access
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Abstract

Summary While many disease-associated variants have been identified through genome-wide association studies, their downstream molecular consequences remain unclear. To identify these effects, we performed cis- and trans-expression quantitative trait locus (eQTL) analysis in blood from 31,684 individuals through the eQTLGen Consortium. We observed that cis -eQTLs can be detected for 88% of the studied genes, but that they have a different genetic architecture compared to disease-associated variants, limiting our ability to use cis -eQTLs to pinpoint causal genes within susceptibility loci. In contrast, trans-eQTLs (detected for 37% of 10,317 studied trait-associated variants) were more informative. Multiple unlinked variants, associated to the same complex trait, often converged on trans-genes that are known to play central roles in disease etiology. We observed the same when ascertaining the effect of polygenic scores calculated for 1,263 genome-wide association study (GWAS) traits. Expression levels of 13% of the studied genes correlated with polygenic scores, and many resulting genes are known to drive these traits.

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