Integrative Genomics Analysis Reveals a Novel 21q22.11 Locus Contributing to Susceptibility of COVID-19

The systematic identification of host genetic risk factors is essential for the understanding and treatment of COVID-19. By performing a meta-analysis of two independent genome-wide association (GWAS) summary datasets (N = 680,128), a novel locus at 21q22.11 was identified to be associated with COVID-19 infection (rs9976829 in IFNAR2 and upstream of IL10RB, OR = 1.16, 95% CI = 1.09 - 1.23, P = 2.57×10⁻⁶). The rs9976829 represents a strong splicing quantitative trait locus (sQTL) for both IFNAR2 and IL10RB genes, especially in lung tissue (P 1.8×10⁻²⁴). Gene-based association analysis also found IFNAR2 was significantly associated with COVID-19 infection (P = 2.58×10⁻⁷). Integrative genomics analysis of combining GWAS with eQTL data showed the expression variations of IFNAR2 and IL10RB have prominent effects on COVID-19 in various types of tissues, especially in lung tissue. The majority of IFNAR2-expressing cells were dendritic cells (40%) and plasmacytoid dendritic cells (38.5%), and IL10RB-expressing cells were mainly nonclassical monocytes (29.6%). IFNAR2 and IL10RB are targeted by several interferons-related drugs. Together, our results uncover 21q22.11 as a novel susceptibility locus for COVID-19, in which individuals with G alleles of rs9976829 have a higher probability of COVID-19 susceptibility than those with non-G alleles.