X-linked multi-ancestry meta-analysis reveals tuberculosis susceptibility variants

Globally, tuberculosis (TB) presents with a clear male bias that cannot be completely accounted for by environment, behaviour, socioeconomic factors, or the impact of sex hormones on the immune system. This suggests that genetic and biological differences, which may be mediated by the X chromosome, further influence the observed male sex bias. The X chromosome is heavily implicated in immune function and yet has largely been ignored in previous association studies. Here we report the first multi-ancestry X chromosome specific meta-analysis on TB susceptibility. We identified X- linked TB susceptibility variants using seven genotyping data sets and 20,255 individuals from diverse genetic ancestries. Sex-specific effects were also identified in polygenic heritability between males and females along with enhanced concordance in direction of genetic effects for males but not females. These sex-specific genetic effects were supported by a sex-stratified and combined meta- analysis conducted using the X chromosome specific XWAS software and a multi-ancestry analysis using the MR-MEGA software. Seven significant associations were identified. Two in the overall analysis (rs6610096, rs7888114) and a second for the female specific analysis (rs4465088) including all data sets. For the ancestry specific meta-analysis three significant associations were identified for males in the Asian cohorts (rs1726176, rs5939510, rs1726203) and one in females for the African cohort (rs2428212). Several genomic regions previously associated with TB susceptibility were reproduced in this study, along with strong ancestry-specific effects. These results support the hypothesis that the X chromosome and sex-specific effects could significantly impact the observed male bias in TB incidence rates globally.