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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2018.00678

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

 Haiko Schurz1, 2*,  Craig Kinnear2, Chris Gignoux3, Genevieve Wojcik4,  Paul D. Van Helden2,  Gerard Tromp2, Brenna Henn5,  Eileen G. Hoal2 and  Marlo Möller2
  • 1Stellenbosch University, South Africa
  • 2South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa., DST-NRF Centre of Excellence for Biomedical Tuberculosis Research (CBTBR), South Africa
  • 3Colorado Center for Personalized Medicine and Department of Biostatistics and Informatics, The Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, United States
  • 4Departments of Genetics, School of Medicine, Stanford University, United States
  • 5Department of Anthropology, UC Davis Genome Center, United States

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 than 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 immune-related genes, supporting the hypothesis that X-linked genes could contribute to TB susceptibility in a sex-biased 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.

Keywords: Tuberculosis, GWAS, Sex-bias, host genetics, X Chromosome, Sex-stratified analysis, susceptibility

Received: 06 Sep 2018; Accepted: 06 Dec 2018.

Edited by:

Zané Lombard, University of the Witwatersrand, South Africa

Reviewed by:

Shigeki Nakagome, Trinity College Dublin, Ireland
Carina M. Schlebusch, Uppsala University, Sweden  

Copyright: © 2018 Schurz, Kinnear, Gignoux, Wojcik, Van Helden, Tromp, Henn, Hoal and Möller. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mr. Haiko Schurz, Stellenbosch University, Stellenbosch, South Africa,