Background:
Recent reports have emerged linking SARS-CoV-2 infection to neurological diseases including stroke. It is unclear whether cerebrovascular disease and SARS-CoV-2 share a common risk mechanism, or whether the specific host response to SARS-CoV-2 increases the risk of stroke. We sought to investigate whether genes and pathways associated with SARS-CoV-2 infection and its systemic host response are also related to risk of ischemic stroke (IS) and intracerebral hemorrhage (ICH).
Methods:
We constructed gene-sets involved with SARS-CoV-2 infection risk and host response. Brain-specific datasets (ROSMAP and Braineac) were used to build co-expression networks for 5 target genes (
ACE2
,
TMPRSS2
,
BEST3
,
ISLR2
and
ADAM17
) involved in SARS-CoV-2 infection phase. Host response gene-sets were constructed from SARS-CoV-2 post-infection gene expression networks measured from lung, kidney, and blood, extracted from literature review. Gene-based association testing was performed using VEGAS2 on GWAS summary data, as well as on data generated through S-PrediXcan analysis of primary tissues relevant to ICH/IS/subtypes. Fisher’s exact test was used to examine gene-set enrichment.
Results:
The SARS-CoV-2 risk-related
ISLR2
co-expression gene network was significantly associated with genetic risk of the large artery stroke (LAS) subtype, across tissues in multiple brain regions (3/10, FDR-p ≤ 0.05), as well as in LAS-relevant primary tissues such as aorta and tibial arteries (p ≤ 0.05). Among SARS-CoV-2 host response factors, SARS-CoV-2 expression changes in lung were found to be enriched for all-cause ischemic stroke risk (p = 0.03), while lobar ICH risk showed an enrichment (p = 0.04) for genes expressed during antiviral response in the blood compartment.
Conclusion:
Gene networks specific to SARS-CoV-2 infection suggest enrichment in pathways related to infection and host response in both IS and ICH, informed by gene expression levels in multiple brain tissues. Collectively, these findings suggest that increases in stroke risk reported in patients with SARS-CoV-2 infection, particularly large artery stroke, may be intrinsic to this viral infection rather than a more generalized response to severe illness.
Cholera host response gene networks: preliminary studies
