Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases.
Accepted version
Peer-reviewed
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Authors
Baird, Denis
Walker, Venexia
Haycock, Philip C
Abstract
The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.
Description
Keywords
Blood Proteins, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Phenotype, Polymorphism, Single Nucleotide, Proteome
Journal Title
Nat Genet
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Journal ISSN
1061-4036
1546-1718
1546-1718
Volume Title
52
Publisher
Springer Science and Business Media LLC
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All rights reserved
Sponsorship
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
British Heart Foundation (RG/18/13/33946)
Medical Research Council (MC_UU_00002/7)
Wellcome Trust (204623/Z/16/Z)
British Heart Foundation (None)
British Heart Foundation (RG/18/13/33946)
Medical Research Council (MC_UU_00002/7)
Wellcome Trust (204623/Z/16/Z)
This publication is the work of the authors and Jie Zheng will serve as guarantor for the contents of this paper. JZ is funded by a Vice-Chancellor Fellowship from the University of Bristol. This research was also funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/1 and MC_UU_00011/4), GlaxoSmithKline, Biogen and the Cancer Research Integrative Cancer Epidemiology Programme (C18281/A19169). The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). GH is funded by the Wellcome Trust and the Royal Society [208806/Z/17/Z]. MVH is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. This study was funded/supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol (GDS and TRG). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Medical Research Council Proximity to Discovery Award. PE is supported by CRUK [C18281/A19169]. SL is funded by the Bau Tsu Zung Bau Kwan Yeun Hing Research and Clinical Fellowship (*200008682.920006.20006.400.01) from the University of Hong Kong. JD is funded by the National Institute for Health Research [Senior Investigator Award]. JD sits on the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010), the Steering Committee of UK Biobank (since 2011), the MRC International Advisory Group (ING) member, London (since 2013), the MRC High Throughput Science ‘Omics Panel Member, London (since 2013), the Scientific Advisory Committee for Sanofi (since 2013), the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis and the Astra Zeneca Genomics Advisory Board (2018).
Participants in the INTERVAL randomised controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping was co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk) and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*]. The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946) and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*]. A complete list of the investigators and contributors to the INTERVAL trial is provided in reference [**]. The academic coordinating centre would like to thank blood donor centre staff and blood donors for participating in the INTERVAL trial.