A phenome-wide bidirectional Mendelian randomization analysis of atrial fibrillation

Qin Wang*, Tom G Richardson, Eleanor C M Sanderson, Mika J Ala-Korpela, George Davey Smith, Michael V Holmes*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

11 Citations (Scopus)
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Abstract

Background
The prevalence of atrial fibrillation (AF) is increasing with an aging worldwide population, yet a comprehensive understanding of its causes and consequences remains limited. We aim to assess the causes and consequences of AF via a bidirectional Mendelian randomization (MR) analysis.

Methods
We used publicly available genome-wide association study (GWAS) summary data, centralized and harmonized by an open GWAS database. We assessed the genetically predicted effects of 5048 exposures on risk of AF, and the genetically predicted effects of genetic liability to AF, on 10 308 outcomes via two-sample MR analysis. Multivariable MR analysis was further conducted to explore the comparative roles of identified risk factors.

Results
MR analysis suggested that 55 out of 5048 exposure traits, including four proteins, play a causal role in AF (P <1e-5 allowing for multiple comparisons). Multivariable analysis suggested that higher body mass index, height and systolic blood pressure as well as genetic liability to coronary artery diseases independently cause AF. Three out of the four proteins (DUSP13, TNFSF12 and IL6R) had a drug prioritizing score for atrial fibrillation of 0.26, 0.38 and 0.88, respectively (values closer to 1 indicating stronger evidence of the protein as a potential drug target). Genetic liability to AF was linked to a higher risk of cardio-embolic ischaemic stroke.

Conclusions
Our results suggest body mass index, height, systolic blood pressure and genetic liability to coronary artery disease are independent causal risk factors for AF. Several proteins, including DUSP13, IL-6R and TNFSF12, may have therapeutic potential for AF.
Original languageEnglish
Article numberdyac041
Pages (from-to)1153-1166
Number of pages14
JournalInternational Journal of Epidemiology
Volume51
Issue number4
DOIs
Publication statusPublished - 15 Mar 2022

Bibliographical note

Funding Information:
Q.W. is supported by a postdoctoral fellowship received from Novo Nordisk Foundation (NNF17OC0027034). G.D.S., E.S., T.G.R., M.J.T. works in a Unit supported by the Medical Research Council for the Integrative Epidemiology Unit (MC-UU-00011/1 at the University of Bristol. M.A.K. was supported by the Sigrid Juselius Foundation. M.V.H. works in a unit that receives funding from the UK Medical Research Council and 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. The views expressed are those of the authors and not necessarily those of funding bodies.

Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press on behalf of the International Epidemiological Association.

Keywords

  • atrial fibrillation
  • mendelian randomization
  • stroke
  • proteins

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