Abstract
BACKGROUND: Tuberculosis (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. METHODS: We 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. FINDINGS: We 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), P (meta) =3.31×10 (-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), P (meta) =4.33×10 (-11) ]. rs6006426 affected SF3A1 expression in various immune cells ( P from 0.003 to 6.17×10 (-18) ) and OSM expression in monocytes post lipopolysaccharide stimulation ( P =5.57×10 (-4) ). CRISPR-Cas9 edited zebrafish embryos with osm depletion resulted in decreased burden of Mycobacterium marinum ( M.marinum ) in infected embryos ( P =0.047). INTERPRETATION: Our findings offer novel insights into the genetic factors underlying TB and reveals new avenues for understanding its etiology.