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.

Evaluation of a Functional Single Nucleotide Polymorphism of the SARS-CoV-2 Receptor ACE2 That Is Potentially Involved in Long COVID

Since the occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, SARS-CoV-2 has led to a global coronavirus disease 2019 (COVID-19) pandemic. A better understanding of the SARS-CoV-2 receptor ACE2 at the genetic level would help combat COVID-19, particularly for long COVID. We performed a genetic analysis of ACE2 and searched for its common potential single nucleotide polymorphisms (SNPs) with minor allele frequency >0.05 in both European and Chinese populations that would contribute to ACE2 gene expression variation. We thought that the variation of the ACE2 expression would be an important biological feature that would strongly affect COVID-19 symptoms, such as “brain fog”, which is highlighted by the fact that ACE2 acts as a major cellular receptor for SARS-CoV-2 attachment and is highly expressed in brain tissues. Based on the human GTEx gene expression database, we found rs2106809 exhibited a significant correlation with the ACE2 expression among multiple brain and artery tissues. This expression correlation was replicated in an independent European brain eQTL database, Braineac. rs2106809*G also displays significantly higher frequency in Asian populations than in Europeans and displays a protective effect (p = 0.047) against COVID-19 hospitalization when comparing hospitalized COVID-19 cases with non-hospitalized COVID-19 or SARS-CoV-2 test-negative samples with European ancestry from the UK Biobank. Furthermore, we experimentally demonstrated that rs2106809*G could upregulate the transcriptional activity of ACE2. Therefore, integrative analysis and functional experiment strongly support that ACE2 SNP rs2106809 is a functional brain eQTL and its potential involvement in long COVID, which warrants further investigation.