PUBLICATION
Genome-wide association study reveals a novel tuberculosis susceptibility locus in multiple East Asian and European populations
- Authors
- Chang, X., Li, Z., Thai, P.V.K., Ha, D.T.M., Thuong, N.T.T., Wee, D., Subhan, A.S.B.M., Silcocks, M., Chee, C.B.E., Nhu, N.T.Q., Heng, C.K., Teo, Y.Y., Singhal, A., Oehlers, S.H., Yuan, J.M., Koh, W.P., Caws, M., Khor, C.C., Dorajoo, R., Dunstan, S.J.
- ID
- ZDB-PUB-260529-21
- Date
- 2026
- Source
- Genome Medicine 18: (Journal)
- Registered Authors
- Oehlers, Stefan, Wee, Denise
- Keywords
- Genome-wide association study, Infectious diseases, Non-HLA genetic locus, Pulmonary tuberculosis, Underrepresented populations
- MeSH Terms
- none
- PubMed
- 42192477 Full text @ Genome Med.
Citation
Chang, X., Li, Z., Thai, P.V.K., Ha, D.T.M., Thuong, N.T.T., Wee, D., Subhan, A.S.B.M., Silcocks, M., Chee, C.B.E., Nhu, N.T.Q., Heng, C.K., Teo, Y.Y., Singhal, A., Oehlers, S.H., Yuan, J.M., Koh, W.P., Caws, M., Khor, C.C., Dorajoo, R., Dunstan, S.J. (2026) Genome-wide association study reveals a novel tuberculosis susceptibility locus in multiple East Asian and European populations. Genome Medicine. 18:.
Abstract
Background Tuberculosis (TB) continues to be a leading cause of morbidity and mortality worldwide. Although numerous genome-wide association studies (GWAS) have explored TB susceptibility across various ethnic groups, multi-population replication of findings has been very limited, particularly outside the HLA region, and 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 (N = 11,841 cases; N = 197,373 controls). The transferability of any identified association was assessed using summary statistics from independent European populations. Potential candidate genes were prioritized using gene-based association testing and integrative bioinformatic database mining, followed by functional validation through assessment of Mycobacterium marinum (M.marinum) infection burden in CRISPR-Cas9-edited zebrafish embryos.
Results 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), Pmeta=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-analysis including a total of 12,736 PTB cases and 673,864 controls [OR (95%Cl) = 1.098 (1.068, 1.129); Pmeta=4.33 × 10- 11]. Gene-based association test identified Oncostatin M (OSM) to be significantly associated with PTB (ZSTAT = 5.013; P = 2.68 × 10- 7; Padj=0.005). The lead SNP rs6006426 affected Splicing factor 3a subunit 1 (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) as reported in the eQTL Catalogue. CRISPR-Cas9 edited zebrafish embryos with osm depletion resulted in decreased burden of M.marinum in infected embryos (P = 0.047).
Conclusions Our findings offer novel insights into the genetic factors underlying TB and reveals new avenues for understanding its etiology.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping