A post-GWAS analysis of predicted regulatory variants and tuberculosis susceptibility

PLoS One. 2017 Apr 6;12(4):e0174738. doi: 10.1371/journal.pone.0174738. eCollection 2017.

Abstract

Utilizing data from published tuberculosis (TB) genome-wide association studies (GWAS), we use a bioinformatics pipeline to detect all polymorphisms in linkage disequilibrium (LD) with variants previously implicated in TB disease susceptibility. The probability that these variants had a predicted regulatory function was estimated using RegulomeDB and Ensembl's Variant Effect Predictor. Subsequent genotyping of these 133 predicted regulatory polymorphisms was performed in 400 admixed South African TB cases and 366 healthy controls in a population-based case-control association study to fine-map the causal variant. We detected associations between tuberculosis susceptibility and six intronic polymorphisms located in MARCO, IFNGR2, ASHAS2, ACACA, NISCH and TLR10. Our post-GWAS approach demonstrates the feasibility of combining multiple TB GWAS datasets with linkage information to identify regulatory variants associated with this infectious disease.

MeSH terms

  • Adult
  • Case-Control Studies
  • Ethnicity / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • South Africa
  • Tuberculosis / genetics*

Grants and funding

This work was supported by the Faculty of Medicine and Health Sciences Early-Career Research Funding for 2015 and the NRF National Bioinformatics Functional Genomics Grant No 93666 to M.M. A.F. and M.W. are supported through the DFG Cluster of Excellence 306 “Inflammation at Interfaces”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.