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

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. In this study, we conducted GWAS in the Singapore Chinese and Vietnamese, followed by a comprehensive meta-analysis incorporating independent East Asian data, and identified a novel pulmonary TB (PTB) susceptibility locus at 22q12.2 [rs6006426, OR(95%Cl)=1.097(1.066, 1.130), P _meta =3.31×10 ^-10 ]. Our lead SNP was found to affect the expression of SF3A1 in various immune-related cells ( P ranging from 1.48×10 ^-9 to 6.17×10 ^{- 18} ). Furthermore, a significant association was observed between rs6006426 and cigarette smoking ( P <0.044). When exploring the interplay between genetic marker, smoking and TB, our findings indicated that smoking status significantly mediated the effect of rs6006426 on PTB (β _{indirect-effect} =-0.004, P _{indirect-effect} =0.020). Our findings offer novel insights into the genetic factors underlying TB and reveals new avenues for understanding its etiology.