Genetic determinants of severe COVID-19 in young Asian and Middle Eastern patients

Studies of genetic factors associated with severe COVID-19 in young adults have been limited in non-Caucasian populations. Here, we use whole exome sequencing to characterize the genetic landscape of severe COVID-19 in a well phenotyped cohort of otherwise healthy, young adults (N=55; mean age 34.1 {+/-} SD 5.0 years) representing 16 countries in Asia, the Middle East, and North Africa. Our findings show enrichment of rare, likely deleterious missense and truncating variants in interferon-mediated and bacterial infection-susceptibility genes, when compared to control, mildly affected, or asymptomatic COVID-19 patients (N = 25), or to general populations representing Asia and the Middle East. Genetic variants tended to associate with mortality, intensive care admission, and ventilation support. Our findings confirm the association of interferon pathway genes with severe COVID-19 and highlight the importance of extending genetic studies to diverse populations given implications for pan-ethnic therapeutic and genetic screening options. Author SummaryBased on the hypothesis that rare monogenic variants contribute to the severity of SARS-CoV-2 infection outcomes, we performed whole exome sequencing in young, previously healthy patients with severe COVID-19 of Asian or Middle Eastern origins. We found an enrichment of rare missense and truncating variants in immune-related genes, mainly associated with interferon pathways and susceptibility to bacterial infections, which can be therapeutic targets. Genetic findings tended to correlate with mortality, intensive care unit (ICU) admission, high dependency unit (HDU) admission, and invasive ventilation.