Leveraging genetic data to elucidate the relationship between Covid-19 and ischemic stroke
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Background
The relationship between coronavirus disease 2019 (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% confidence interval 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.
The relationship between coronavirus disease 2019 (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% confidence interval 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.
Date Issued
2021-11-10
Date Acceptance
2021-09-23
Citation
Journal of the American Heart Association, 2021, 10 (22), pp.1-24
ISSN
2047-9980
Publisher
Wiley
Start Page
1
End Page
24
Journal / Book Title
Journal of the American Heart Association
Volume
10
Issue
22
Copyright Statement
© 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Sponsor
Commission of the European Communities
Identifier
https://www.ahajournals.org/doi/10.1161/JAHA.121.022433
Grant Number
101016072
Subjects
Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Cardiovascular System & Cardiology
COVID-19
cross-trait linkage disequilibrium score regression
ischemic stroke
Mendelian randomization
GENOME-WIDE ASSOCIATION
MENDELIAN RANDOMIZATION
RISK
INSTRUMENTS
OUTBREAK
BIAS
COVID‐19
Mendelian randomization
cross‐trait linkage disequilibrium score regression
ischemic stroke
Body Mass Index
Brain Ischemia
C-Reactive Protein
COVID-19
Genome-Wide Association Study
Humans
Inflammation
Ischemic Stroke
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
Risk Factors
Smoking
Humans
Brain Ischemia
Inflammation
C-Reactive Protein
Body Mass Index
Risk Factors
Smoking
Polymorphism, Single Nucleotide
Genome-Wide Association Study
Mendelian Randomization Analysis
COVID-19
Ischemic Stroke
1102 Cardiorespiratory Medicine and Haematology
Publication Status
Published
Date Publish Online
2021-11-10