TY - JOUR
T1 - Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits
AU - Porcu, Eleonora
AU - Rüeger, Sina
AU - Lepik, Kaido
AU - Agbessi, Mawussé
AU - Ahsan, Habibul
AU - Alves, Isabel
AU - Andiappan, Anand
AU - Arindrarto, Wibowo
AU - Awadalla, Philip
AU - Battle, Alexis
AU - Beutner, Frank
AU - Jan Bonder, Marc
AU - Christiansen, Mark
AU - Claringbould, Annique
AU - Deelen, Patrick
AU - Esko, Tõnu
AU - Favé, Marie Julie
AU - Franke, Lude
AU - Frayling, Timothy
AU - Gharib, Sina A.
AU - Gibson, Gregory
AU - Heijmans, Bastiaan T.
AU - Hemani, Gibran
AU - Jansen, Rick
AU - Kähönen, Mika
AU - Kalnapenkis, Anette
AU - Kasela, Silva
AU - Kettunen, Johannes
AU - Kim, Yungil
AU - Kirsten, Holger
AU - Kovacs, Peter
AU - Krohn, Knut
AU - Kronberg-Guzman, Jaanika
AU - Kukushkina, Viktorija
AU - Lee, Bernett
AU - Lehtimäki, Terho
AU - Loeffler, Markus
AU - Marigorta, Urko M.
AU - Mei, Hailang
AU - Milani, Lili
AU - Montgomery, Grant W.
AU - Müller-Nurasyid, Martina
AU - Nauck, Matthias
AU - Penninx, Brenda
AU - Perola, Markus
AU - Pervjakova, Natalia
AU - Pierce, Brandon L.
AU - Powell, Joseph
AU - Prokisch, Holger
AU - Psaty, Bruce M.
AU - Raitakari, Olli T.
AU - Ripatti, Samuli
AU - Rotzschke, Olaf
AU - Saha, Ashis
AU - Scholz, Markus
AU - Schramm, Katharina
AU - Seppälä, Ilkka
AU - Slagboom, Eline P.
AU - Stehouwer, Coen D.A.
AU - Stumvoll, Michael
AU - Sullivan, Patrick
AU - ’t Hoen, Peter A.C.
AU - Teumer, Alexander
AU - Thiery, Joachim
AU - Tong, Lin
AU - Tönjes, Anke
AU - van Dongen, Jenny
AU - van Iterson, Maarten
AU - van Meurs, Joyce
AU - Veldink, Jan H.
AU - Verlouw, Joost
AU - Visscher, Peter M.
AU - Völker, Uwe
AU - Võsa, Urmo
AU - Westra, Harm Jan
AU - Wijmenga, Cisca
AU - Yaghootkar, Hanieh
AU - Yang, Jian
AU - Zeng, Biao
AU - Zhang, Futao
AU - Arindrarto, Wibowo
AU - Beekman, Marian
AU - Bot, Jan
AU - Deelen, Joris
AU - Deelen, Patrick
AU - Franke, Lude
AU - Heijmans, Bastiaan T.
AU - ’t Hoen, Peter A.C.
AU - Hofman, Bert A.
AU - Isaacs, Aaron
AU - Bonder, Marc Jan
AU - Jhamai, P. Mila
AU - Jansen, Rick
AU - Kielbasa, Szymon M.
AU - Lakenberg, Nico
AU - Luijk, René
AU - Mei, Hailiang
AU - Moed, Matthijs
AU - Nooren, Irene
AU - Schalkwijk, Casper G.
AU - Slagboom, P. Eline
AU - Stehouwer, Coen D.A.
AU - Suchiman, H. Eka D.
AU - Swertz, Morris A.
AU - Tigchelaar, Ettje F.
AU - Uitterlinden, André G.
AU - van den Berg, Leonard H.
AU - van der Breggen, Ruud
AU - van der Kallen, Carla J.H.
AU - van Dijk, Freerk
AU - van Duijn, Cornelia M.
AU - van Galen, Michiel
AU - van Greevenbroek, Marleen M.J.
AU - van Heemst, Diana
AU - van Iterson, Maarten
AU - van Meurs, Joyce
AU - van Rooij, Jeroen
AU - van’t Hof, Peter
AU - van Zwet, Erik W.
AU - Vermaat, Martijn
AU - Veldink, Jan H.
AU - Verbiest, Michael
AU - Verkerk, Marijn
AU - Wijmenga, Cisca
AU - Zhernakova, Dasha V.
AU - Zhernakova, Sasha
AU - Santoni, Federico A.
AU - Reymond, Alexandre
AU - Kutalik, Zoltán
AU - eQTLGen Consortium
AU - BIOS Consortium
AU - Boomsma, D.I.
AU - Nivard, Michel G.
AU - Hottenga, Jouke Jan
AU - Pool, René
AU - van Dongen, Jenny
PY - 2019/7/24
Y1 - 2019/7/24
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-10936-0
DO - 10.1038/s41467-019-10936-0
M3 - Article
AN - SCOPUS:85069729041
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3300
ER -