Molecular Biology and Human Genetics

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Browsing Molecular Biology and Human Genetics by Subject "Africa -- Polpulation"

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    Genome-Wide Associations Between Human Genotypes and Mycobacterium tuberculosis Clades Causing Disease
    (Stellenbosch : Stellenbosch University, 2019-03) Pitts, Stephanie Julia; Kinnear, Craig; Moller, Marlo; Hoal, Eileen; Van der Spuy, Gian; Tromp, Gerard; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences: Molecular Biology and Human Genetics.
    ENGLISH ABSTRACT: The World Health Organization (WHO) declared tuberculosis (TB) to be a global health emergency in 1993, and despite decades of extensive biomedical research, it remains a major cause of morbidity and mortality around the world. A disease primarily affecting the lungs, TB manifests following infection with a pathogenic member of the Mycobacterium tuberculosis (M. tb) Complex (MTBC) such as M.africanum and M. tb, although infection alone is not sufficient for disease. Each member of theMTBC consists of several strains (or clades), with variable virulence and disease-causing mechanisms. M.africanum is the main cause of TB in West African countries including Ghana, while M. tb isresponsible for TB cases in most other parts of the world, with stratification of clades by geographical location. TB is a multifactorial disease, influenced by environmental factors, bacterial virulence, and the genetic susceptibility of the host. While the genetic susceptibility of the host to the tuberculous disease has been extensively studied using genome-wide association studies and candidate gene studies, no method currently exists to perform an association analysis between the genetic architecture of the host and the susceptibility to the many clades of M. tb or M. africanum causing disease. Two geographically distinct cohorts were included in this study: a cohort of 947 participants self-identifying as belonging to the five-way admixed South African Coloured (SAC) population with paired infecting M. tb isolate information was used to establish the protocol for performing the association analysis, while a second cohort consisting of 3 311 participants recruited in Ghana was used to validate this method. The method developed includes quality control filters on both the host genotype data, and the infecting isolate database. Thereafter, haplotype phasing and genotype imputation of several reference panels was performed to increase the number of single nucleotide polymorphisms (SNPs) available for association testing. An assessment of imputation quality scores revealed the best imputation reference panel for the study cohort and a multinomial logistic regression (MLR) analysis was performed to assess potential associations between host genotypes and infecting bacterial clades of multiple classes. Here, we demonstrated that the African Genome Resource (used via the Sanger Imputation Server) produced the highest quality of imputed genotype data for the SAC cohort, while the 1000 Genomes Phase 3 reference panel was the best reference panel for the Ghanaian cohort. MLR was performed while controlling for covariates including age, sex, and ancestry proportions. After genotype imputation, 445 SAC - and 1 272 Ghanaian participants passed quality control and were tested for association to five- and six infecting superclades, respectively. Models of association revealed no SNPs reaching genome-wide significance for the SAC cohort, while 32 SNPs met the GWAS cut-off of 5 x 10-8 for the Ghanaian cohort. For the Ghanaian cohort, the risk allele of SNP rs551641937 (g.62385889G>A), located on chromosome 15, was determined to increase the risk of TB caused by the EAI/AFRI superclade by 276 times, when compared to the LAMCAM reference superclade. The emphasis of the dissertation was to perform an association analysis using host genotype and pathogen data and finding the best reference panel for imputing each of the two datasets was a secondary aim. This study demonstrates the first method successfully testing host-genotype associations with multiple clades of M. tb isolates causing disease.