Leveraging genetic data to elucidate the relationship between COVID‐19 and ischemic stroke

Zuber, V., Cameron, A., Myserlis, E. P., Bottolo, L., Fernandez‐Cadenas, I., Burgess, S., Anderson, C. D., Dawson, J. and Gill, D. (2021) Leveraging genetic data to elucidate the relationship between COVID‐19 and ischemic stroke. Journal of the American Heart Association, 10(22), e022433. (doi: 10.1161/JAHA.121.022433) (PMID:34755518)

Abstract

Background: The relationship between COVID‐19 and ischemic stroke is poorly understood due to potential unmeasured confounding and reverse causation. We aimed to leverage genetic data to triangulate reported associations. Methods and Results: Analyses primarily focused on critical COVID‐19, defined as hospitalization with COVID‐19 requiring respiratory support or resulting in death. Cross‐trait linkage disequilibrium score regression was used to estimate genetic correlations of critical COVID‐19 with ischemic stroke, other related cardiovascular outcomes, and risk factors common to both COVID‐19 and cardiovascular disease (body mass index, smoking and chronic inflammation, estimated using C‐reactive protein). Mendelian randomization analysis was performed to investigate whether liability to critical COVID‐19 was associated with increased risk of any cardiovascular outcome for which genetic correlation was identified. There was evidence of genetic correlation between critical COVID‐19 and ischemic stroke (rg=0.29, false discovery rate [FDR]=0.012), body mass index (rg=0.21, FDR=0.00002), and C‐reactive protein (rg=0.20, FDR=0.00035), but no other trait investigated. In Mendelian randomization, liability to critical COVID‐19 was associated with increased risk of ischemic stroke (odds ratio [OR] per logOR increase in genetically predicted critical COVID‐19 liability 1.03, 95% CI 1.00–1.06, P‐value=0.03). Similar estimates were obtained for ischemic stroke subtypes. Consistent estimates were also obtained when performing statistical sensitivity analyses more robust to the inclusion of pleiotropic variants, including multivariable Mendelian randomization analyses adjusting for potential genetic confounding through body mass index, smoking, and chronic inflammation. There was no evidence to suggest that genetic liability to ischemic stroke increased the risk of critical COVID‐19. Conclusions: These data support that liability to critical COVID‐19 is associated with an increased risk of ischemic stroke. The host response predisposing to severe COVID‐19 is likely to increase the risk of ischemic stroke, independent of other potentially mitigating risk factors.

• Item Type: Articles
• Additional Information: VZ is supported by UK Dementia Research Institute at Imperial College London, which is funded by the Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK (MC_PC_17114). The research leading to these results has been conducted as part of the COVIRNA project (grant agreement n°101016072) funded by the European Union’s Horizon 2020 Framework Programme for Research and Innovation. EPM is supported by the National Institutes of Health of the United States (R01NS103924, U01NS069763). LB acknowledges the MRC grant MR/S02638X/1, The BHF‐Turing Cardiovascular Data Science Awards 2017 and The Alan Turing Institute under the Engineering and Physical Sciences Research Council grant EP/N510129/1. IF‐C is supported by Inmungen‐Cov2 project, Centro Superior de Investigaciones Científicas (CSIC). SB is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z). This research was supported by the UKRI Medical Research Council [MC_UU_00002/7] and the NIHR Cambridge Biomedical Research Centre (BRC‐1215‐20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. CDA is supported by the National Institutes of Health of the United States (R01NS103924, U01NS069763). DG is supported by the British Heart Foundation Centre of Research Excellence at Imperial College London (RE/18/4/34215) and by a National Institute for Health Research Clinical Lectureship at St. George's, University of London (CL‐2020‐16‐001). This research was funded in part by the Wellcome Trust.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Dawson, Professor Jesse and Cameron, Dr Alan
• Authors: Zuber, V., Cameron, A., Myserlis, E. P., Bottolo, L., Fernandez‐Cadenas, I., Burgess, S., Anderson, C. D., Dawson, J., and Gill, D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Journal of the American Heart Association
• Publisher: Wiley
• ISSN: 2047-9980
• ISSN (Online): 2047-9980
• Published Online: 10 November 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Journal of the American Heart Association 10(22):e022433
• Publisher Policy: Reproduced under a Creative Commons License