title: A post-GWAS analysis of predicted regulatory variants and tuberculosis susceptibility.
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.
authors.affiliation: SA MRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Caitlin
authors.identifier: http://orcid.org/0000-0003-2358-0135
authors.initials: C
authors.lastname: Uren
authors.affiliation: Department of Ecology and Evolution, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Brenna M
authors.initials: BM
authors.lastname: Henn
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Rosalind-Franklin-Strasse Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Rosalind-Franklin-Strasse Kiel, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wittig
authors.affiliation: SA MRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Paul D
authors.initials: PD
authors.lastname: van Helden
authors.affiliation: SA MRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Eileen G
authors.initials: EG
authors.lastname: Hoal
authors.affiliation: SA MRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Marlo
authors.initials: M
authors.lastname: Möller
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005006:Ethnicity / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013019:South Africa; D014376:Tuberculosis / Q000235:genetics*