Common variants at 22q12.2 are associated with susceptibility to Tuberculosis

BackgroundTuberculosis (TB) continues to be a leading cause of morbidity and mortality worldwide. Past genome-wide association studies (GWAS) have explored TB susceptibility across various ethnic groups, yet a significant portion of TB heritability remains unexplained. MethodsWe conducted GWAS in the Singapore Chinese and Vietnamese, followed by a comprehensive meta-analysis incorporating 4 independent East Asian datasets, resulting in a total of 11,841 cases and 197,373 population controls. FindingsWe identified a novel susceptibility locus for pulmonary TB (PTB) at 22q12.2 in East Asians [rs6006426, OR (95%Cl) =1.097(1.066, 1.130), Pmeta=3.31x10-10]. The association was further validated in Europeans [OR (95%Cl) =1.101(1.002, 1.211), P=0.046] and was strengthened in the combined meta-anlaysis including 12,736 PTB cases and 673,864 controls [OR (95%Cl) =1.098(1.068, 1.129), Pmeta=4.33x10-11]. rs6006426 affected SF3A1 expression in various immune cells (P from 0.003 to 6.17x10-18) and OSM expression in monocytes post lipopolysaccharide stimulation (P=5.57x10-4). CRISPR-Cas9 edited zebrafish embryos with osm depletion resulted in decreased burden of Mycobacterium marinum (M.marinum) in infected embryos (P=0.047). InterpretationOur findings offer novel insights into the genetic factors underlying TB and reveals new avenues for understanding its etiology.