Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases oflife-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remainto be identified in ~ 80% of cases.Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients withlife-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-riskvariants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P = 1.1 × 10-4) for biochemically loss-of-function (bLOF)variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involvedin TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3-8.2], P = 2.1 × 10-4). This enrichment was furtherstrengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model(OR = 19.65[95%CI 2.1-2635.4], P = 3.4 × 10-3), and (2) considering as pLOF branchpoint variants with potentiallystrong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3-8.4], P = 7.7 × 10-8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients(56.0 [17.3] years; P = 1.68 × 10-5).Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threateningCOVID-19, particularly with recessive inheritance, in patients under 60 years old.