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

Caitlin Uren,Brenna M Henn,Marlo Möller,Eileen G Hoal,Michael Wittig,Paul D Van Helden,Andre Franke

doi:10.1371/journal.pone.0174738

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.

Highlights

Genome-wide association studies (GWAS) have advanced the investigation of complex disease genetics and identified thousands of disease-associated variants
GWAS is based on the premise that causal variants will be in linkage disequilibrium (LD) with the markers present on single nucleotide polymorphism (SNP) arrays
Data mining identified 1800 SNPs that were found to be in LD (r2 > 0.8) with the 230 SNPs previously associated with TB

Summary

Introduction

Genome-wide association studies (GWAS) have advanced the investigation of complex disease genetics and identified thousands of disease-associated variants. Since 2005, when the first GWAS was published [1], associations have been detected between numerous common genetic variants and several infectious diseases including TB [2,3,4,5]. Thye et al (2010) performed the first GWAS on TB susceptibility in a case-control cohort from Ghana and the Gambia and identified a region on chromosome 18q11.2 [6]. Within this region, there are numerous immune response genes such as cadherin 13 (CDH13), zinc finger protein 229 (ZNF229) and exportin 1 (XPO1).

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Conclusion