Leveraging genetic data to elucidate the relationship between Covid-19 and ischemic stroke

Zuber, Verena; Cameron, Alan; Myserlis, Evangelos P.; Bottolo, Leonardo; Fernandez-Cadenas, Israel; Burgess, Stephen; Anderson, Christopher D.; Dawson, Jesse; Gill, Dipender

BACKGROUND: The relationship between coronavirus disease 2019 (Covid-19) and ischemic stroke is poorly defined. We aimed to leverage genetic data to investigate reported associations. METHODS: Genetic association estimates for liability to Covid-19 and cardiovascular traits were obtained from large-scale consortia. 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 of the cardiovascular outcomes for which genetic correlation was identified. RESULTS: There was evidence of genetic correlation between critical Covid-19 and ischemic stroke (r(g)=0.29, FDR p-value=4.65×10(−3)), body mass index (r(g)=0.21, FDR-p-value=6.26×10(−6)) and C-reactive protein (r(g)=0.20, FDR-p-value=1.35×10(−4)), but none of the other considered traits. In Mendelian randomization analysis, 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 when considering 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.