Human Genomics of COVID-19 Pneumonia: Contributions of Rare and Common Variants

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is silent or benign in most infected individuals, but causes hypoxemic COVID-19 pneumonia in about 10% of cases. We review studies of the human genetics of life-threatening COVID-19 pneumonia, focusing on both rare and common variants. Large-scale genome-wide association studies have identified more than 20 common loci robustly associated with COVID-19 pneumonia with modest effect sizes, some implicating genes expressed in the lungs or leukocytes. The most robust association, on chromosome 3, concerns a haplotype inherited from Neanderthals. Sequencing studies focusing on rare variants with a strong effect have been particularly successful, identifying inborn errors of type I interferon (IFN) immunity in 1-5% of unvaccinated patients with critical pneumonia, and their autoimmune phenocopy, autoantibodies against type I IFN, in another 15-20% of cases. Our growing understanding of the impact of human genetic variation on immunity to SARS-CoV-2 is enabling health systems to improve protection for individuals and populations.

Automated summary

SARS-CoV-2 infection can be asymptomatic or mild in most cases, but around 10% of individuals develop hypoxemic COVID-19 pneumonia. Studies on human genetics have identified both rare and common variants associated with life-threatening COVID-19 pneumonia. Large-scale genome-wide association studies have found over 20 common loci linked to COVID-19 pneumonia, some involving genes expressed in the lungs or leukocytes. The strongest association, on chromosome 3, involves a haplotype inherited from Neanderthals. Sequencing studies focusing on rare variants have successfully identified inborn errors of type I interferon (IFN) immunity in 1-5% of unvaccinated patients with critical pneumonia, and autoantibodies against type I IFN in another 15-20% of cases. Understanding the impact of human genetic variation on SARS-CoV-2 immunity helps improve protection in individuals and populations.