![]() Mendelian randomization (MR) can be employed to investigate whether genetic variants predicting an exposure (such as COVID‐19) also associate with risk of an outcome (such as ischemic stroke). Cross‐trait linkage disequilibrium score regression (LDSC) can be used to estimate the genetic correlation between traits. Leverage of genetic data can help overcome some of these issues. 12 Similarly, patients with acute stroke have a dampened immune response and may be more susceptible to severe COVID‐19. 3, 4, 5, 6 For example, there are common risk factors for severe COVID‐19 and stroke, such as obesity and smoking. 9, 10 Obtaining unbiased estimates for the risk of stroke in people with COVID‐19 is challenging due to difficulty diagnosing mild COVID‐19 and an overall reduction in the rate of admission to hospital with stroke, and minor stroke in particular, during the pandemic, 9, 11 Furthermore, observational studies investigating the association between COVID‐19 and stroke are vulnerable to potential confounding and reverse causation. 8 However, some studies do not support an increased risk of stroke in individuals with COVID‐19. ![]() 6, 7 Indeed, almost two‐fifths of people with COVID‐19 who develop stroke consequently die. 5 Strokes that occur in individuals with COVID‐19 are more severe, have poorer outcomes, and higher mortality rates than in those without COVID‐19, despite similar acute management. 3, 4, 5, 6 This has been estimated to be seven times greater than in influenza infection, 3 with up to 5% of people with severe COVID‐19 suffering stroke. 1, 2 While much of the disease burden relates to respiratory failure and sepsis, some studies suggest an increased risk of ischemic stroke. SARS‐CoV‐2 infection is the cause of the COVID‐19 pandemic that has resulted in a health crisis of unprecedented magnitude. ![]() The host response predisposing to severe COVID‐19 is likely to increase the risk of ischemic stroke, independent of other potentially mitigating risk factors. These data support that liability to critical COVID‐19 is associated with an increased risk of ischemic stroke. There was no evidence to suggest that genetic liability to ischemic stroke increased the risk of critical COVID‐19. ![]() 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. Similar estimates were obtained for ischemic stroke subtypes. In Mendelian randomization, liability to critical COVID‐19 was associated with increased risk of ischemic stroke (odds ratio per logOR increase in genetically predicted critical COVID‐19 liability 1.03, 95% CI 1.00–1.06, P‐value=0.03). There was evidence of genetic correlation between critical COVID‐19 and ischemic stroke (r g=0.29, false discovery rate =0.012), body mass index (r g=0.21, FDR=0.00002), and C‐reactive protein (r g=0.20, FDR=0.00035), but no other trait investigated. 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. 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). Stroke: Vascular and Interventional NeurologyĪnalyses primarily focused on critical COVID‐19, defined as hospitalization with COVID‐19 requiring respiratory support or resulting in death.Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes.Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB).
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