Genome-Wide Association Study of Sepsis Susceptibility in ICU Patients Identifies Arab Founder Loss-of-Function Variant in UBE2L3

Sepsis causes approximately 11 million deaths globally each year. Whole-genome sequencing (WGS) of founder populations offers a unique opportunity for discovery of genes related to susceptibility of sepsis. We performed GWAS and EXWAS on WGS data for n=210 Arab ICU patients (n=68 sepsis cases, n=142 controls, other ICU-related disorders) and prioritized n=40 associated deleterious founder variants in n=31 genes (REGENIE Firth regression p 20; enriched AAF vs AllofUs/gnomAD), including a novel start-loss variant in UBE2L3 (c.2T>G; p.Met1?; CADD = 25.6; SIFT = 0.001) in sepsis cases (3/68 vs 0/142 controls; Fishers exact P = 0.026). In All of Us (AoU), UBE2L3 missense burden was associated with bacterial infection (n=26,939 cases; SKAT-O P = 2.38x10-3; OR=23.10; 95% CI = [0.63-845.27]). LLM AI models fine-tuned for drug development scored UBE2L3 a 7.8 of 10 as a drug target for sepsis, consistent with mouse UBE2L3 KO showing increased IL-1Beta mediated inflammation in sepsis.