Shared genetic background between SARS-CoV-2 infection and large artery stroke.
Int J Stroke. 2022 Apr 11:17474930221095696. doi: 10.1177/17474930221095696. Epub ahead of print. PMID: 35403514.
|Authors/Editors:||Parodi L, Myserlis EP, Chung J, Georgakis M, Mayerhofer E, Henry J, Montgomery B, Moy M, Xu H, Malik R, Langefeld C, Dichgans M, Woo D, Rosand J, Anderson CD.|
Background and aims: Increased risk of stroke, particularly large artery stroke (LAS), has been observed in patients with COVID-19. The biological processes underlying the observed higher risk are still unknown. We explored the association between stroke subtypes and COVID-19 susceptibility to understand whether biological mechanisms specific to SARS-CoV-2 uptake/infection could be leading to excess stroke risk in this population.
Patients and methods: We constructed a polygenic risk score (PRS) of COVID-19 susceptibility and tested its association with stroke subtypes using individual- and summary-level genetic data (SiGN, MEGASTROKE). We generated co-expression networks of genes involved in SARS-CoV-2 uptake/infection (ACE2, TMPRSS2, BEST3, ISLR2 and ADAM17) based on existing tissue expression libraries. Gene-based association testing was performed using S PrediXcan and VEGAS2. Permutation independence tests were performed to assess SARS CoV-2-related gene enrichment in stroke and its subtypes.
Results: Our PRS demonstrated an association between COVID-19 susceptibility and LAS in SiGN (OR=1.05 per SD increase, 95% CI: [1.00, 1.10], p=0.04) and MEGASTROKE (β=0.510, 95% CI: [0.242, 0.779], FDR-p = 0.0019). The SARS-CoV-2 risk-related ISLR2 co-expression gene network was significantly associated with genetic risk of LAS in aorta, tibial arteries, and multiple brain regions (P < 0.05).
Conclusion: Presence of genetic correlation and significant pathway enrichment suggest that increases in LAS risk reported in COVID-19 patients may be intrinsic to the viral infection, rather than a more generalized response to severe illness.
Data access statement: The data and the code that support the findings of this study are available from the authors upon reasonable request.