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Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

2019; Nature Portfolio; Volume: 10; Issue: 1 Linguagem: Inglês

10.1038/s41467-019-10936-0

2041-1723

Eleonora Porcu, Sina Rüeger, Kaido Lepik, Mawussé Agbessi, Habibul Ahsan, Isabel Alves, Anand Kumar Andiappan, Wibowo Arindrarto, Philip Awadalla, Alexis Battle, Frank Beutner, Marc Jan Bonder, Dorret I. Boomsma, Mark Christiansen, Annique Claringbould, Patrick Deelen, Tõnu Esko, Marie-Julie Favé, Lude Franke, Timothy M. Frayling, Sina A. Gharib, Gregory Gibson, Bastiaan T. Heijmans, Gibran Hemani, Rick Jansen, Mika Kähönen, Anette Kalnapenkis, Silva Kasela, Johannes Kettunen, Yungil Kim, Holger Kirsten, Péter Kovács, Knut Krohn, Jaanika Kronberg-Guzman, Viktorija Kukushkina, Bernett Lee, Terho Lehtimäki, Markus Loeffler, Urko M. Marigorta, Hailang Mei, Lili Milani, Grant W. Montgomery, Martina Müller‐Nurasyid, Matthias Nauck, Michel G. Nivard, Brenda W.J.H. Penninx, Markus Perola, Natalia Pervjakova, Brandon L. Pierce, Joseph E. Powell, Holger Prokisch, Bruce M. Psaty, Olli T. Raitakari, Samuli Ripatti, Olaf Rötzschke, Ashis Saha, Markus Scholz, Katharina Schramm, Ilkka Seppälä, P. Eline Slagboom, Coen D.A. Stehouwer, Michael Stümvoll, Patrick Sullivan, Peter A.C. ‘t Hoen, Alexander Teumer, Joachim Thiery, Tong Lin, Anke Tönjes, Jenny van Dongen, Maarten van Iterson, Joyce B. J. van Meurs, Jan H. Veldink, Joost Verlouw, Peter M. Visscher, Uwe Völker, Urmo Võsa, Harm-Jan Westra, Cisca Wijmenga, Hanieh Yaghootkar, Jian Yang, Biao Zeng, Futao Zhang, Wibowo Arindrarto, Marian Beekman, Dorret I. Boomsma, Jan Bot, Joris Deelen, Patrick Deelen, Lude Franke, Bastiaan T. Heijmans, Peter A.C. ‘t Hoen, Bert A. Hofman, Jouke‐Jan Hottenga, Aaron Isaacs, Marc Jan Bonder, P. Mila Jhamai, Rick Jansen, Szymon M. Kiełbasa, Nico Lakenberg, René Luijk, Hailiang Mei, Matthijs Moed, Irene Nooren, René Pool, Casper G. Schalkwijk, P. Eline Slagboom, Coen D.A. Stehouwer, H. Eka D. Suchiman, Morris A. Swertz, Ettje F. Tigchelaar, André G. Uitterlinden, Leonard H. van den Berg, Ruud van der Breggen, Carla Kallen, Freerk van Dijk, Jenny van Dongen, Cornelia M. van Duijn, Michiel van Galen, Marleen M. J. van Greevenbroek, Diana van Heemst, Maarten van Iterson, Joyce B. J. van Meurs, Jeroen van Rooij, Peter van’t Hof, Erik W. van Zwet, Martijn Vermaat, Jan H. Veldink, Michaël Verbiest, Marijn Verkerk, Cisca Wijmenga, Dasha V. Zhernakova, Sasha Zhernakova, Federico Santoni, Alexandre Reymond, Zoltán Kutalik,

Genetic Syndromes and Imprinting

Abstract Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2 , known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.