Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis

作者：Urmo Võsa, Annique Claringbould, Harm-Jan Westra, Marc Jan Bonder, Patrick Deelen, Biao Zeng, Holger Kirsten, Ashis Saha, Roman Kreuzhuber, Silva Kasela, Natalia Pervjakova, Isabel Alvaes, Marie-Julie Favé, Mawussé Agbessi, Mark Christiansen, Rick Jansen, Ilkka Seppälä, Tong Lin, Alexander Teumer, Katharina Schramm, Gibran Hemani, Joost Verlouw, Hanieh Yaghootkar, Reyhan Sönmez, Andrew Brown, Viktorija Kukushkina, Anette Kalnapenkis, Sina Rüeger, Eleonora Porcu, Jaanika Kronberg-Guzman, Johannes Kettunen, Joseph E. Powell, Bernett Lee, Futao Zhang, Wibowo Arindrarto, Frank Beutner, Harm Brugge, Julia Dmitreva, Mahmoud Elansary, Benjamin P. Fairfax, Michel Georges, Bastiaan T. Heijmans, Mika Kähönen, Yungil Kim, Julian C. Knight, Péter Kovács, Knut Krohn, Shuang� Li, Markus Loeffler, Urko M. Marigorta, Hailang Mei, Yukihide Momozawa, Martina Müller‐Nurasyid, Matthias Nauck, Michel G. Nivard, Brenda W.J.H. Penninx, Jonathan K. Pritchard, Olli T. Raitakari, Olaf Rotzchke, P. Eline Slagboom, Coen D.A. Stehouwer, Michael Stümvoll, Patrick Sullivan, Peter A.C. ’t Hoen, Joachim Thiery, Anke Tönjes, Jenny van Dongen, Maarten van Iterson, Jan H. Veldink, Uwe Völker, Cisca Wijmenga, Morris A. Swertz, Anand Kumar Andiappan, Grant W. Montgomery, Samuli Ripatti, Markus Perola, Zoltán Kutalik, Emmanouil T. Dermitzakis, Sven Bergmann, Timothy M. Frayling, Joyce B. J. van Meurs, Holger Prokisch, Habibul Ahsan, Brandon L. Pierce, Terho Lehtimäki, Dorret I. Boomsma, Bruce M. Psaty, Sina A. Gharib, Philip Awadalla, Lili Milani, Willem H. Ouwehand, Kate Downes, Oliver Stegle, Alexis Battle, Jian Yang, Peter M. Visscher, Markus Scholz, Gregory Gibson, Tõnu Esko, Lude Franke · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2018 · DOI：10.1101/447367 · 被引用次数：550 · 研究领域：Genetic Associations and Epidemiology、Bioinformatics and Genomic Networks、Genetic Mapping and Diversity in Plants and Animals

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.