MAP3K19 regulatory variation in populations with African ancestry is associated with severe COVID-19 (preprint)

Ancestry impacts the likelihood of hospitalization due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). To identify ancestry-linked genetic risk variants associated with COVID-19 hospitalization, we performed an integrative analysis of two genome-wide association studies (GWASs) evaluating genetic variation among ancestrally diverse cohorts. We resolved four single nucleotide polymorphisms (SNPs) that are more frequent in COVID-19 hospitalized patients with non-European ancestry than the general population. Among them, the COVID-19 risk SNP rs16831827 shows the largest difference in allele frequency between African and European populations. The minor allele frequency of rs16831827*T was significantly higher in hospitalized COVID-19 patients with African ancestry. SNP rs16831827 also associates with COVID-19 hospitalization in an independent GWAS from the UK Biobank wherein both the hospitalized and control patients are entirely of African ancestry. rs16831827 is an expression quantitative trait locus (eQTL) of MAP3K19. Apart from rs16831827, two rare SNPs of MAP3K19, rs186150828 and rs192473276, were also significantly associated with COVID-19 hospitalization among African populations in the Regeneron COVID-19 hospitalization GWAS (p < 5x10-7). MAP3K19 expression is induced during ciliogenesis and most abundant in ciliated tissues including the lung and testis. Multiple COVID-19 related single-cell RNA sequencing data revealed that MAP3K19 is highly expressed in nasal multiciliated epithelial cells, nasopharyngeal ciliated cells, and airway ciliated cells. The COVID-19 hospitalization risk allele rs16831827*T is associated with reduced MAP3K19 expression. Hence, rs16831827 may increase the risk of severe COVID-19 by reducing baseline MAP3K19 expression.

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

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.