Genetic Screening for Hypertension and COVID-19 Reveals Functional Variation of Potentially Associated with Severe COVID-19 in Women

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 6.4 million deaths worldwide. The prevalent comorbidity between hypertension and severe COVID-19 suggests common genetic factors may affect the outcome of both diseases. As both hypertension and severe COVID-19 demonstrate sex-biased prevalence, common genetic factors between the two diseases may display sex-biased differential associations. By evaluating COVID-19 association signals of 172-candidate hypertension single nucleotide polymorphisms (SNPs) derived from more than 1 million European individuals in two sex-stratified severe COVID-19 genome-wide association studies from UK BioBank with European ancestry, we revealed one functional cis expression quantitative trait locus of (rs12474050) showing sex-biased association with severe COVID-19 in women. The risk allele rs12474050*T associates with higher blood pressure. In our study, we found it is significantly correlated with lower expression in muscle-skeletal but with higher expression in both brain cerebellum and cerebellar hemisphere. Additionally, nominal significances were detected for the association between rs12474050*T and lower expression in both heart left ventricle and atrial appendage; among these tissues, the expression is nominally significantly higher in females than in males. Further analysis revealed is mainly expressed in cardiomyocytes in heart and is upregulated upon SARS-CoV-2 infection, with significantly higher upregulation of only observed in female but not in male COVID-19 patients compared to both normal female and male individuals, suggesting upregulation of is a female-specific protective mechanism against COVID-19 induced heart damage. Taken together, our analyses suggest the involvement of in both hypertension and severe COVID-19 in women, which provides new insights for sex-biased effect of severe COVID-19 in women.