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

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Article number3300
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 24 Jul 2019

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genome
Genome-Wide Association Study
Random Allocation
determinants
Genes
Single Nucleotide Polymorphism
gene expression
Gene expression
Statistics
statistics
Gene Expression Regulation
Brain Diseases
Transcriptome
phenotype
loci
mutations
Genome
Phenotype
Gene Expression
Mutation

Cite this

@article{0ae2c2dbfbc54d76b9450b9d93d3702e,
title = "Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits",
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.",
author = "Eleonora Porcu and Sina R{\"u}eger and Kaido Lepik and Mawuss{\'e} Agbessi and Habibul Ahsan and Isabel Alves and Anand Andiappan and Wibowo Arindrarto and Philip Awadalla and Alexis Battle and Frank Beutner and {Jan Bonder}, Marc and Mark Christiansen and Annique Claringbould and Patrick Deelen and T{\~o}nu Esko and Fav{\'e}, {Marie Julie} and Lude Franke and Timothy Frayling and Gharib, {Sina A.} and Gregory Gibson and Heijmans, {Bastiaan T.} and Gibran Hemani and Rick Jansen and Mika K{\"a}h{\"o}nen and Anette Kalnapenkis and Silva Kasela and Johannes Kettunen and Yungil Kim and Holger Kirsten and Peter Kovacs and Knut Krohn and Jaanika Kronberg-Guzman and Viktorija Kukushkina and Bernett Lee and Terho Lehtim{\"a}ki and Markus Loeffler and Marigorta, {Urko M.} and Hailang Mei and Lili Milani and Montgomery, {Grant W.} and Martina M{\"u}ller-Nurasyid and Matthias Nauck and Brenda Penninx and Markus Perola and Natalia Pervjakova and Pierce, {Brandon L.} and Joseph Powell and Holger Prokisch and Psaty, {Bruce M.} and Raitakari, {Olli T.} and Samuli Ripatti and Olaf Rotzschke and Ashis Saha and Markus Scholz and Katharina Schramm and Ilkka Sepp{\"a}l{\"a} and Slagboom, {Eline P.} and Stehouwer, {Coen D.A.} and Michael Stumvoll and Patrick Sullivan and {’t Hoen}, {Peter A.C.} and Alexander Teumer and Joachim Thiery and Lin Tong and Anke T{\"o}njes and {van Dongen}, Jenny and {van Iterson}, Maarten and {van Meurs}, Joyce and Veldink, {Jan H.} and Joost Verlouw and Visscher, {Peter M.} and Uwe V{\"o}lker and Urmo V{\~o}sa and Westra, {Harm Jan} and Cisca Wijmenga and Hanieh Yaghootkar and Jian Yang and Biao Zeng and Futao Zhang and Wibowo Arindrarto and Marian Beekman and Jan Bot and Joris Deelen and Patrick Deelen and Lude Franke and Heijmans, {Bastiaan T.} and {’t Hoen}, {Peter A.C.} and Hofman, {Bert A.} and Aaron Isaacs and Bonder, {Marc Jan} and Jhamai, {P. Mila} and Rick Jansen and Kielbasa, {Szymon M.} and Nico Lakenberg and Ren{\'e} Luijk and Hailiang Mei and Matthijs Moed and Irene Nooren and Schalkwijk, {Casper G.} and Slagboom, {P. Eline} and Stehouwer, {Coen D.A.} and Suchiman, {H. Eka D.} and Swertz, {Morris A.} and Tigchelaar, {Ettje F.} and Uitterlinden, {Andr{\'e} G.} and {van den Berg}, {Leonard H.} and {van der Breggen}, Ruud and {van der Kallen}, {Carla J.H.} and {van Dijk}, Freerk and {van Duijn}, {Cornelia M.} and {van Galen}, Michiel and {van Greevenbroek}, {Marleen M.J.} and {van Heemst}, Diana and {van Iterson}, Maarten and {van Meurs}, Joyce and {van Rooij}, Jeroen and {van’t Hof}, Peter and {van Zwet}, {Erik W.} and Martijn Vermaat and Veldink, {Jan H.} and Michael Verbiest and Marijn Verkerk and Cisca Wijmenga and Zhernakova, {Dasha V.} and Sasha Zhernakova and Santoni, {Federico A.} and Alexandre Reymond and Zolt{\'a}n Kutalik and {eQTLGen Consortium} and {BIOS Consortium} and D.I. Boomsma and Michel Nivard and Hottenga, {Jouke Jan} and Ren{\'e} Pool and {van Dongen}, Jenny",
year = "2019",
month = "7",
day = "24",
doi = "10.1038/s41467-019-10936-0",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits. / eQTLGen Consortium; BIOS Consortium ; Boomsma, D.I.; Nivard, Michel; Hottenga, Jouke Jan ; Pool, René; van Dongen, Jenny.

In: Nature Communications, Vol. 10, No. 1, 3300, 24.07.2019.

Research output: Contribution to JournalArticleAcademicpeer-review

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

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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JO - Nature Communications

JF - Nature Communications

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