Genetic screening for hypertension and COVID-19 reveals functional variant of SPEG associated with severe COVID-19 in female

Abstract The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused more than 6.4 million deaths worldwide and is still spreading among global populations. 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-specific prevalence, common genetic factors among the two diseases may display gender-based differential associations. By evaluating COVID-19 association signals of 172-candidate hypertension single nucleotide polymorphisms derived from more than one million European individuals in two severe COVID-19 genome-wide association studies from UK BioBank with European ancestry, we revealed one functional cis expression quantitative trait locus of SPEG (rs12474050) associating with both hypertension and severe COVID-19 in female. The risk allele of rs12474050*T is correlated with lower SPEG expression in muscle-skeletal, heart-atrial appendage, and heart-left ventricle; among these tissues the SPEG expression is higher in female than in male COVID-19 patients. Further analysis revealed SPEG is mainly expressed in cardiomyocytes in heart and is upregulated upon SARS-CoV-2 infection, with significantly higher folder change of SPEG expression observed in female compared to male COVID-19 patients. Taken together, our analyses strongly suggest the involvement of SPEG in both hypertension and severe COVID-19 in female, which provides new insights for sex-specific effect of severe COVID-19 in female.