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

Journal article

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.

Authors: Chang, X; Li, Z; Thai, PVK; Ha, DTM; Thuong, NTT

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BioMed Central
• Journal: Genome Medicine
• Volume: 18
• Issue: 1
• Article number: 71
• Publication date: 2026-05-27
• Acceptance date: 2026-05-12
• DOI: 10.1186/s13073-026-01670-6
• EISSN: 1756-994X
• ISSN: 1756-994X
• Language: English
• Keywords: Genome-wide association study; Infectious diseases; Non-HLA genetic locus; Underrepresented populations; Pulmonary tuberculosis