Multi-omics highlights ABO plasma protein as a causal risk factor for COVID-19

SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) and the current health crisis. Despite intensive research efforts, the genes and pathways that contribute to COVID-19 remain poorly understood. We therefore used an integrative genomics (IG) approach to identify candidate genes responsible for COVID-19 and its severity. We used Bayesian colocalization (COLOC) and summary-based Mendelian randomization to combine gene expression quantitative trait loci (eQTLs) from the Lung eQTL (n=1,038) and eQTLGen (n=31,784) studies with published COVID-19 genome-wide association study (GWAS) data from the COVID-19 Host Genetics Initiative. Additionally, we used COLOC to integrate plasma protein quantitative trait loci (pQTL) from the INTERVAL study (n=3,301) with COVID-19-associated loci. Finally, we determined any causal associations between plasma proteins and COVID-19 using multi-variable two-sample Mendelian randomization (MR). We found that the expression of 20 genes in lung and 31 genes in blood was associated with COVID-19. Of these genes, only three (LZTFL1, SLC6A20 and ABO) had been previously linked with COVID-19 in GWAS. The novel loci included genes involved in interferon pathways (IL10RB, IFNAR2 and OAS1). Plasma ABO protein, which is associated with blood type in humans, demonstrated a significant causal relationship with COVID-19 in MR analysis; increased plasma levels were associated with an increased risk of having COVID-19 and risk of severe COVID-19. In summary, our study identified genes associated with COVID-19 that may be prioritized for future investigation. Importantly, this is the first study to demonstrate a causal association between plasma ABO protein and COVID-19.