Genome-wide association study of ancestry-specific TB risk in the South African Coloured population

Hum Mol Genet. 2014 Feb 1;23(3):796-809. doi: 10.1093/hmg/ddt462. Epub 2013 Sep 20.

Abstract

The worldwide burden of tuberculosis (TB) remains an enormous problem, and is particularly severe in the admixed South African Coloured (SAC) population residing in the Western Cape. Despite evidence from twin studies suggesting a strong genetic component to TB resistance, only a few loci have been identified to date. In this work, we conduct a genome-wide association study (GWAS), meta-analysis and trans-ethnic fine mapping to attempt the replication of previously identified TB susceptibility loci. Our GWAS results confirm the WT1 chr11 susceptibility locus (rs2057178: odds ratio = 0.62, P = 2.71e(-06)) previously identified by Thye et al., but fail to replicate previously identified polymorphisms in the TLR8 gene and locus 18q11.2. Our study demonstrates that the genetic contribution to TB risk varies between continental populations, and illustrates the value of including admixed populations in studies of TB risk and other complex phenotypes. Our evaluation of local ancestry based on the real and simulated data demonstrates that case-only admixture mapping is currently impractical in multi-way admixed populations, such as the SAC, due to spurious deviations in average local ancestry generated by current local ancestry inference methods. This study provides insights into identifying disease genes and ancestry-specific disease risk in multi-way admixed populations.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • African Continental Ancestry Group / genetics*
  • Case-Control Studies
  • Cytoplasmic Dyneins / genetics
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genetics, Population
  • Genome-Wide Association Study
  • HapMap Project
  • Humans
  • Male
  • Polymorphism, Single Nucleotide
  • South Africa
  • Tuberculosis / genetics*
  • WT1 Proteins / genetics

Substances

  • DYNC2H1 protein, human
  • WT1 Proteins
  • WT1 protein, human
  • Cytoplasmic Dyneins