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Background <p>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.</p> Methods <p>We conducted GWAS in the Singapore Chinese and Vietnamese, followed by a comprehensive meta-analysis incorporating 4 independent East Asian datasets (<i>N</i> = 11,841 cases; <i>N</i> = 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 <i>Mycobacterium marinum</i> (<i>M.marinum</i>) infection burden in CRISPR-Cas9-edited zebrafish embryos.</p> Results <p>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), <i>P</i><sub><i>meta</i></sub>=3.31 × 10<sup>− 10</sup>]. The association was further validated in Europeans [OR (95%Cl) = 1.101(1.002, 1.211), <i>P</i> = 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); <i>P</i><sub><i>meta</i></sub>=4.33 × 10<sup>− 11</sup>]. Gene-based association test identified Oncostatin M (<i>OSM</i>) to be significantly associated with PTB (ZSTAT = 5.013; <i>P</i> = 2.68 × 10<sup>− 7</sup>; <i>P</i><sub><i>adj</i></sub>=0.005). The lead SNP rs6006426 affected Splicing factor 3a subunit 1 (<i>SF3A1</i>) expression in various immune cells (<i>P</i> from 0.003 to 6.17 × 10<sup>− 18</sup>) and <i>OSM</i> expression in monocytes post lipopolysaccharide stimulation (<i>P</i> = 5.57 × 10<sup>− 4</sup>) as reported in the eQTL Catalogue. CRISPR-Cas9 edited zebrafish embryos with <i>osm</i> depletion resulted in decreased burden of <i>M.marinum</i> in infected embryos (<i>P</i> = 0.047).</p> Conclusions <p>Our findings offer novel insights into the genetic factors underlying TB and reveals new avenues for understanding its etiology.</p>

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

  • 期刊论文

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  • 发表日期：

    2026年5月27日

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  • Xuling Chang,
  • Zheng Li,
  • Phan Vuong Khac Thai,
  • Dang Thi Minh Ha,
  • Nguyen Thuy Thuong Thuong,
  • Denise Wee,
  • Alya Sufiyah Binte Mohamed Subhan,
  • Matthew Silcocks,
  • Cynthia Bin Eng Chee,
  • Nguyen Thi Quynh Nhu,
  • Chew-Kiat Heng,
  • Yik Ying Teo,
  • Amit Singhal,
  • Stefan H Oehlers,
  • Jian-Min Yuan,
  • Woon-Puay Koh,
  • Maxine Caws,
  • Chiea Chuen Khor,
  • Rajkumar Dorajoo,
  • Sarah J Dunstan

摘要

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.