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), Pmeta=3.31x10-10]. Our lead SNP was found to affect the expression of SF3A1 in various immune-related cells (P ranging from 1.48x10-9 to 6.17x10-18). 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 (betaindirect-effect=-0.004, Pindirect-effect=0.020). Our findings offer novel insights into the genetic factors underlying TB and reveals new avenues for understanding its etiology. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the National Health and Medical Research Council, Australia (Investigator grant APP1172853 to SJD); NHMRC (APP1056689) /A*STAR (12/1/21/24/6689) joint call to SJD/YYT; the USA National Institute of Health (U19AI162583 to SJD); This research was funded by Wellcome in whole, or in part (research training fellowship 081814/Z/06/Z to MC, 206724/Z/17/Z to NTTT and 089276/Z/09/Z to Major Overseas Program in Vietnam). The Singapore Chinese Health Study was supported by the National Institutes of Health (NIH) of the United States (Grants R01CA080205, R01CA144034, and UM1CA182876 to J-MY) and the National Medical Research Council, Singapore (NMRC/CIRG/1456/2016). W-P Koh was supported by the National Medical Research Council, Singapore [CSA-SI (MOH-000434)]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: SCHS was approved by the Institutional Review Board at the National University of Singapore, and written informed consent was obtained from all study participants. The study included Vietnamese was approved by the institutional Review Boards of the Hospital for Tropical Diseases HCMC Vietnam, Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease HCMC Vietnam, Health Services of HCMC Vietnam, the Oxford Tropical Research Ethics Committee, Oxford University UK and the University of Melbourne Human Research Ethics Committee, Melbourne Australia (ID 21973). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Summary statistics for PTB GWAS in Singaporean Chinese and Vietnamese will be available in figshare on publication.