Genome-wide association study reveals a novel tuberculosis susceptibility locus in multiple East Asian and European populations.

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),=3.31×10]. The association was further validated in Europeans [OR (95%Cl) =1.101(1.002, 1.211),=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),=4.33×10]. rs6006426 affectedexpression in various immune cells (from 0.003 to 6.17×10) andexpression in monocytes post lipopolysaccharide stimulation (=5.57×10). CRISPR-Cas9 edited zebrafish embryos withdepletion resulted in decreased burden of() in infected embryos (=0.047).

INTERPRETATION: Our findings offer novel insights into the genetic factors underlying TB and reveals new avenues for understanding its etiology.