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by a sex-stratified and combined meta-analysis conducted us..., This analysis includes 7 of the 17 published (and unpublished) GWAS studies of TB (with HIV-negative cohorts) prior to 2022. It excludes data from Iceland and Vietnam, as they declined to share data. It excludes data from China, Korea, Peru, and Japan, as data-sharing agreements could not be finalized in time for this analysis. The Indonesian data was not suitable for reliable imputation, and the Moroccan data was family-based and thus also not suitable for this meta-analysis. Data from Thailand, Japan, Estonia and Germany were excluded as they did not have X chromosome genotyping. Finally, genotyped TB cases and controls are also available in the UK Biobank, but this data was not included in this analysis as genetic association studies on such highly selected datasets need to be undertaken with caution, and to not bias results, were excluded for this analysis.
Included individuals were genotyped on a variety of genotyping arrays, and raw genotyping data were available for eight dataset..., , # X-linked multi-ancestry meta-analysis reveals tuberculosis susceptibility variants

[https://doi.org/10.5061/dryad.2z34tmpv5](https://doi.org/10.5061/dryad.2z34tmpv5)

For this X-chromosome specific sex-stratified meta-analysis multiple analysis were conducted. First, we did sex-stratified association analysis on all the individual datasets using the XWAS software and then the results were combined in multiple meta-analysis (also using XWAS). The results for the individual datasets are not available in this repository but can be requested through the corresponding authors in the published manuscript. The results for the meta-analysis are available in this repository. Multiple meta-analysis was conducted, a combined meta-analysis and a sex stratified meta-analysis, which were also further stratified by the source population subgroup. The following meta-analysis were conducted:

1.      A combined meta-analysis using data across all populations for males and females.   

2.      A sex-s...