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

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State: Public
Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_5BC4DEF5ED27
Type
Article: article from journal or magazin.
Collection
Publications
Title
Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits.
Journal
Nature communications
Author(s)
Porcu E., Rüeger S., Lepik K., Santoni F.A., Reymond A., Kutalik Z.
Working group(s)
eQTLGen Consortium, BIOS Consortium
Contributor(s)
Agbessi M., Ahsan H., Alves I., Andiappan A., Arindrarto W., Awadalla P., Battle A., Beutner F., Jan Bonder M., Boomsma D., Christiansen M., Claringbould A., Deelen P., Esko T., Favé M.J., Franke L., Frayling T., Gharib S.A., Gibson G., Heijmans B.T., Hemani G., Jansen R., Kähönen M., Kalnapenkis A., Kasela S., Kettunen J., Kim Y., Kirsten H., Kovacs P., Krohn K., Kronberg-Guzman J., Kukushkina V., Lee B., Lehtimäki T., Loeffler M., Marigorta U.M., Mei H., Milani L., Montgomery G.W., Müller-Nurasyid M., Nauck M., Nivard M., Penninx B., Perola M., Pervjakova N., Pierce B.L., Powell J., Prokisch H., Psaty B.M., Raitakari O.T., Ripatti S., Rotzschke O., Saha A., Scholz M., Schramm K., Seppälä I., Slagboom E.P., Stehouwer CDA, Stumvoll M., Sullivan P., 't Hoen PAC, Teumer A., Thiery J., Tong L., Tönjes A., van Dongen J., van Iterson M., van Meurs J., Veldink J.H., Verlouw J., Visscher P.M., Völker U., Võsa U., Westra H.J., Wijmenga C., Yaghootkar H., Yang J., Zeng B., Zhang F., Arindrarto W., Beekman M., Boomsma D.I., Bot J., Deelen J., Deelen P., Franke L., Heijmans B.T., 't Hoen PAC, Hofman B.A., Hottenga J.J., Isaacs A., Bonder M.J., Jhamai P.M., Jansen R., Kielbasa S.M., Lakenberg N., Luijk R., Mei H., Moed M., Nooren I., Pool R., Schalkwijk C.G., Slagboom P.E., Stehouwer CDA, Suchiman HED, Swertz M.A., Tigchelaar E.F., Uitterlinden A.G., van den Berg L.H., van der Breggen R., van der Kallen CJH, van Dijk F., van Dongen J., van Duijn C.M., van Galen M., van Greevenbroek MMJ, van Heemst D., van Iterson M., van Meurs J., van Rooij J., Van't Hof P., van Zwet E.W., Vermaat M., Veldink J.H., Verbiest M., Verkerk M., Wijmenga C., Zhernakova D.V., Zhernakova S.
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Publication state
Published
Issued date
24/07/2019
Peer-reviewed
Oui
Volume
10
Number
1
Pages
3300
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
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.
Keywords
Brain Diseases/genetics, GTP-Binding Protein gamma Subunits, Gene Expression Profiling, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Transcriptome
Pubmed
Web of science
Open Access
Yes
Create date
06/08/2019 17:43
Last modification date
18/02/2020 7:20
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