Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture

The heritability of susceptibility to tuberculosis disease (TB) has been well recognized. Over one-hundred genes have been studied as candidates for TB susceptibility, and several variants were identified by genome-wide association studies (GWAS), but few replicate. We established the International Tuberculosis Host Genetics Consortium (ITHGC) to perform a multi-ancestry meta-analysis of GWAS including 14153 cases and 19536 controls of African, Asian, and European ancestry. Our analyses demonstrate a substantial degree of heritability (pooled polygenic h²=26.3% 95% CI 23.7-29.0%) for susceptibility to TB that is shared across ancestries, highlighting an important host genetic influence on disease. We identified one global host genetic correlate for TB at genome-wide significance (p<5×10⁻⁸) in the human leukocyte antigen (HLA)-II region (rs28383206, p-value = 5.2×10⁻⁹). These data demonstrate the complex shared genetic architecture of susceptibility to TB and the importance of large scale GWAS analysis across multiple ancestries experiencing different levels of infection pressures.