University of Oulu

Porcu, E., Rüeger, S., Lepik, K. et al. Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits. Nat Commun 10, 3300 (2019). https://doi.org/10.1038/s41467-019-10936-0

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

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Author: Porcu, Eleonora1,2; Rueger, Sina2,3; Lepik, Kaido3,4;
Agbessi, Mawusse5; Ahsan, Habibul6; Alves, Isabel5; Andiappan, Anand7; Arindrarto, Wibowo8,9; Awadalla, Philip5; Battle, Alexis10,11; Beutner, Frank12; Bonder, Marc Jan13,14,15; Boomsma, Dorret16; Christiansen, Mark17; Claringbould, Annique13; Deelen, Patrick13,18; Esko, Tonu19; Fave, Marie-Julie11; Franke, Lude13; Frayling, Timothy20; Gharib, Sina A.17,21; Gibson, Gregory22; Heijmans, Bastiaan T.8,23; Hemani, Gibran24; Jansen, Rick25; Kahonen, Mika26,27; Kalnapenkis, Anette19; Kasela, Silva19; Kettunen, Johannes28; Kim, Yungil11,29; Kirsten, Holger30; Kovacs, Peter31; Krohn, Knut32; Kronberg-Guzman, Jaanika19; Kukushkina, Viktorija19; Lee, Bernett7; Lehtimaki, Terho33,34; Loeffler, Markus30; Marigorta, Urko M.22; Mei, Hailang8; Milani, Lili19; Montgomery, Grant W.35; Mueler-Nurasyid, Martina36,37,38; Nauck, Matthias39; Nivard, Michel16; Penninx, Brenda26,27; Perola, Markus40; Pervjakova, Natalia19; Pierce, Brandon L.6; Powell, Joseph41; Prokisch, Holger42,43; Psaty, Bruce M.17,44,21,45,46; Raitakari, Olli T.47,48; Ripatti, Samuli49; Rotzschke, Olaf7; Saha, Ashis11; Scholz, Markus30; Schramm, Katharina38,39; Seppala, Ilkka33,34; Slagboom, Eline P.8; Stehouwer, Coen D. A.50; Stumvoll, Michael51; Sullivan, Patrick52; Teumer, Alexander53; Thiery, Joachim54; Tong, Lin6; Tonjes, Anke51; van Dongen, Jenny16; van Iterson, Maarten8,23; van Meurs, Joyce55; Veldink, Jan H.56; Verlouw, Joost55; Visscher, Peter M.35; Volker, Uwe57; Vosa, Urmo13,19; Westra, Harm-Jan13; Wijmenga, Cisca13; Yaghootkar, Hanieh20; Yang, Jian35,58; Zeng, Biao22; Zhang, Futao35; Arindrarto, Wibowo8,9; Beekman, Marian23; Boomsma, Dorret I.16; Bot, Jan59; Deelen, Joris23; Deelen, Patrick13,18; Franke, Lude13; Heijmans, Bastiaan T.8,23; Hofman, Bert A.60; Hottenga, Jouke J.16; Isaacs, Aaron61; Bonder, Marc Jan13,14,15; Jhamai, P. Mila3; Jansen, Rick25; Kielbasa, Szymon M.62; Lakenberg, Nico23; Luijk, Rene23; Mei, Hailiang9; Moed, Matthijs23; Nooren, Irene59; Pool, Rene16; Schalkwijk, Casper G.50,63; Slagboom, P. Eline23; Stehouwer, Coen D. A.50; Suchiman, H. Eka D.23; Swertz, Morris A.18; Tigchelaar, Ettje F.13; Uitterlinden, Andre G.55; van den Berg, Leonard H.59; van der Breggen, Ruud23; van der Kallen, Carla J. H.50,63; van Dijk, Freerk18; van Dongen, Jenny16; van Duijn, Cornelia M.61; van Galen, Michiel; van Greevenbroek, Marleen M. J.50,63; van Heemst, Diana64; van Iterson, Maarten8,23; van Meurs, Joyce55; van Rooij, Jeroen55; Van't Hof, Peter9; van Zwet, Erik. W.62; Vermaat, Martijn; Veldink, Jan H.56; Verbiest, Michael55; Verkerk, Marijn55; Wijmenga, Cisca13; Zhernakova, Dasha V.13; Zhernakova, Sasha13; Santoni, Federico A.65,66; Reymond, Alexandre1; Kutalik, Zoltan2,3
Organizations: 1Univ Lausanne, Ctr Integrat Genom, Lausanne, Switzerland.
2Swiss Inst Bioinformat, Lausanne, Switzerland.
3Univ Lausanne, Univ Ctr Primary Care & Publ Hlth, Lausanne, Switzerland.
4Univ Tartu, Inst Comp Sci, Tartu, Estonia.
5Ontario Inst Canc Res, Computat Biol, Toronto, ON, Canada.
6Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA.
7Agcy Sci Technol & Res, Singapore Immunol Network, Singapore, Singapore.
8Leiden Univ, Med Ctr, Dept Biomed Data Sci, Leiden, Netherlands.
9Leiden Univ, Med Ctr, Sequence Anal Support Core, Leiden, Netherlands.
10Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA.
11Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA.
12Univ Leipzig, Heart Ctr Leipzig, Leipzig, Germany.
13Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
14European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Hinxton, England.
15European Mol Biol Lab, Genome Biol Unit, Heidelberg, Germany.
16Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands.
17Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.
18Univ Med Ctr Groningen, Genom Coordinat Ctr, Groningen, Netherlands.
19Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
20Univ Exeter, Exeter Med Sch, Exeter EX2 5DW, Devon, England.
21Univ Washington, Dept Med, Seattle, WA USA.
22Georgia Tech, Sch Biol Sci, Atlanta, GA USA.
23Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, Mol Epidemiol Sect, NL-2333 ZA Leiden, Netherlands.
24Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England.
25Vrije Univ, Amsterdam UMC, Dept Psychiat & Amsterdam Neurosci, Amsterdam, Netherlands.
26Tampere Univ, Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland.
27Tampere Univ, Fac Med & Hlth Technol, Tampere, Finland.
28Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland.
29Icahn Sch Med Mt Sinai, Genet & Genom Sci Dept, New York, NY 10029 USA.
30Univ Leipzig, Inst Med Informat Stat & Epidemiol, LIFE Leipzig Res Ctr Civilizat Dis, Leipzig, Germany.
31Univ Leipzig, IFB Adipos Dis, Leipzig, Germany.
32Univ Leipzig, Interdisciplinary Ctr Clin Res, Fac Med, Leipzig, Germany.
33Tampere Univ, Fimlab Labs, Dept Clin Chem, Tampere, Finland.
34Tampere Univ, Finnish Cardiovasc Res Ctr Tampere, Fac Med & Hlth Technol, Tampere, Finland.
35Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia.
36German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.
37Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Dept Med 1, Munich, Germany.
38Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany.
39Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany.
40Univ Helsinki, Natl Inst Hlth & Welf, Helsinki, Finland.
41Garvan Weizmann Ctr Cellular Genom, Garvan Inst Med Res, Sydney, NSW, Australia.
42Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany.
43Tech Univ Munich, Inst Human Genet, Munich, Germany.
44Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.
45Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA.
46Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA.
47Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Ctr Populat Hlth Res, Turku, Finland.
48Univ Turku, Turku, Finland.
49Univ Helsinki, Stat & Translat Genet, Helsinki, Finland.
50Maastricht Univ, Med Ctr, Dept Internal Med, Maastricht, Netherlands.
51Univ Leipzig, Dept Med, Leipzig, Germany.
52Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
53Univ Med Greifswald, Inst Community Med, Greifswald, Germany.
54Univ Leipzig, LIFE Leipzig Res Ctr Civilizat Dis, Inst Lab Med, Leipzig, Germany.
55Erasmus MC, Dept Internal Med, Rotterdam, Netherlands.
56Univ Med Ctr Utrecht, Dept Neurol, Utrecht, Netherlands.
57Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany.
58Wenzhou Med Univ, Inst Adv Res, Wenzhou 325027, Zhejiang, Peoples R China.
59SURFsara, Amsterdam, Netherlands.
60ErasmusMC, Dept Epidemiol, Rotterdam, Netherlands.
61ErasmusMC, Dept Genet Epidemiol, Rotterdam, Netherlands.
62Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, Med Stat Sect, Leiden, Netherlands.
63Maastricht Univ, Med Ctr, Sch Cardiovasc Dis CARIM, Maastricht, Netherlands.
64Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands.
65CHU Vaudois, Endocrine Diabet & Metab Serv, Lausanne, Switzerland.
66Univ Lausanne, Lausanne, Switzerland.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe202003117859
Language: English
Published: Springer Nature, 2019
Publish Date: 2020-03-11
Description:

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.

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Series: Nature communications
ISSN: 2041-1723
ISSN-E: 2041-1723
ISSN-L: 2041-1723
Volume: 10
Article number: 3300
DOI: 10.1038/s41467-019-10936-0
OADOI: https://oadoi.org/10.1038/s41467-019-10936-0
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3141 Health care science
Subjects:
Funding: This work was supported by grants from the Swiss National Science Foundation (31003A_143914 and 32003B_173092 to ZK and 31003A_160203 to AR) and the Horizon2020 Twinning project ePerMed (692145 to AR). This research has been conducted using the UK Biobank Resource (#16389). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Copyright information: © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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