University of Oulu

Wang, Q., Richardson, T. G., Sanderson, E., Tudball, M. J., Ala-Korpela, M., Davey Smith, G., & Holmes, M. V. (2022). A phenome-wide bidirectional Mendelian randomization analysis of atrial fibrillation. International Journal of Epidemiology, 51(4), 1153–1166. https://doi.org/10.1093/ije/dyac041

A phenome-wide bidirectional Mendelian randomization analysis of atrial fibrillation

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Author: Wang, Qin1,2,3,4; Richardson, Tom G.2,5,6; Sanderson, Eleanor2,5;
Organizations: 1Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
2Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK
3Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
4Center for Life Course Health Research, University of Oulu, Oulu, Finland
5Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
6Novo Nordisk Research Centre Oxford, Oxford, UK
7NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
8Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, UK
9National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 4.3 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022112566963
Language: English
Published: Oxford University Press, 2022
Publish Date: 2022-11-25
Description:

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.

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Series: International journal of epidemiology
ISSN: 0300-5771
ISSN-E: 1464-3685
ISSN-L: 0300-5771
Volume: 51
Issue: 4
Pages: 1153 - 1166
DOI: 10.1093/ije/dyac041
OADOI: https://oadoi.org/10.1093/ije/dyac041
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
3111 Biomedicine
Subjects:
Funding: 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.
Dataset Reference: Data are publicly available at [https://gwas.mrcieu.ac.uk].
  https://gwas.mrcieu.ac.uk
Copyright information: © The Author(s) 2022. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
  https://creativecommons.org/licenses/by/4.0/