A sex-stratified genome-wide association study of tuberculosis using a multi-ethnic genotyping array

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a complex disease with a known human genetic component. Males seem to be more affected than females and in most countries the TB notification rate is twice as high in males as in females. While socio-economic status, behaviour and sex hormones influence the male bias they do not fully account for it. Males have only one copy of the X chromosome, while diploid females are subject to X chromosome inactivation. In addition, the X chromosome codes for many immunerelated genes, supporting the hypothesis that X-linked genes could contribute to TB susceptibility in a sexbiased manner. We report the first TB susceptibility genome-wide association study (GWAS) with a specific focus on sex-stratified autosomal analysis and the X chromosome. Individuals from an admixed South African population were genotyped using the Illumina Multi Ethnic Genotyping Array, specifically designed as a suitable platform for diverse and admixed populations. Association testing was done on the autosome and X chromosome in a sex stratified and combined manner. SNP association testing was not statistically significant using a stringent cut-off for significance but revealed likely candidate genes that warrant further investigation.A genome wide interaction analysis detected 16 significant interactions. Finally, the results highlight the importance of sex-stratified analysis as strong sex-specific effects were identified on both the autosome and X chromosome.

Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

“…It is more likely to be >10, as shown by the data for the infected control simulation, corresponding to a lifetime risk of TB between 40 and 80%. This OR is higher than those reported for the few SNPs identified by genome-wide association studies (GWAS) in TB (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). These 12 GWAS did not detect the effect of P1104A, as they did not report testing a recessive model.…”

CLEC4E (Mincle) genetic variation associates with pulmonary tuberculosis in Guinea-Bissau (West Africa)

“…The PTB cases were significantly younger than controls (36.86 years vs 39.17 years), and there was an excess of males (60.9%). This sex differential is expected and has been previously reported (Jaillon et al, 2019;Schurz et al, 2018). Six common ethnic groups were identified in the study group by consisting of at least 5% of the overall collected population (Table 1).…”

Evaluating the Accuracy of Imputation Methods in a Five-Way Admixed Population

“…Genotype data obtained using the Affymetrix and MEGA arrays were subjected to iterative quality control (QC) using PLINK v1.9 (Purcell et al, 2007; Chang et al, 2015) as previously described (Schurz et al, 2018), with the exception of related individuals not being removed. Individuals missing more than 10% genotype information and SNPs with more than 2% missingness were removed, as well as any variants with a minor allele frequency (MAF) below 5% as well as loci with excessive heterozygosity (a detailed description of the filtering process can be found in Supplementary Data S3).…”