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.