Browsing by Author "Daya, Michelle"

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    Determining ancestry proportions in complex admixture scenarios in South Africa using a novel proxy ancestry selection method
    (PLoS, 2013-09) Chimusa, Emile R.; Daya, Michelle; Möller, Marlo; Ramesar, Raj; Henn, Brenna M.; Van Helden, Paul D.; Mulder, Nicola J.; Hoal, Eileen G.
    Admixed populations can make an important contribution to the discovery of disease susceptibility genes if the parental populations exhibit substantial variation in susceptibility. Admixture mapping has been used successfully, but is not designed to cope with populations that have more than two or three ancestral populations. The inference of admixture proportions and local ancestry and the imputation of missing genotypes in admixed populations are crucial in both understanding variation in disease and identifying novel disease loci. These inferences make use of reference populations, and accuracy depends on the choice of ancestral populations. Using an insufficient or inaccurate ancestral panel can result in erroneously inferred ancestry and affect the detection power of GWAS and meta-analysis when using imputation. Current algorithms are inadequate for multi-way admixed populations. To address these challenges we developed PROXYANC, an approach to select the best proxy ancestral populations. From the simulation of a multi-way admixed population we demonstrate the capability and accuracy of PROXYANC and illustrate the importance of the choice of ancestry in both estimating admixture proportions and imputing missing genotypes. We applied this approach to a complex, uniquely admixed South African population. Using genome-wide SNP data from over 764 individuals, we accurately estimate the genetic contributions from the best ancestral populations: isiXhosa (33%±0:226), {Khomani SAN (31%±0:195), European (16%±0:118), Indian (13%±0:094), and Chinese (7%±0:0488). We also demonstrate that the ancestral allele frequency differences correlate with increased linkage disequilibrium in the South African population, which originates from admixture events rather than population bottlenecks.
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    Investigating the role of gene-gene interactions in TB susceptibility
    (Public Library of Science, 2015-04) Daya, Michelle; Van der Merwe, Lize; Van Helden, Paul D.; Moller, Marlo; Hoal, Eileen G.
    Tuberculosis (TB) is the second leading cause of mortality from infectious disease worldwide. One of the factors involved in developing disease is the genetics of the host, yet the field of TB susceptibility genetics has not yielded the answers that were expected. A commonly posited explanation for the missing heritability of complex disease is gene-gene interactions, also referred to as epistasis. In this study we investigate the role of gene-gene interactions in genetic susceptibility to TB using a cohort recruited from a high TB incidence community from Cape Town, South Africa. Our discovery data set incorporates genotypes from a large a number of candidate gene studies as well as genome-wide data. After limiting our search space to pairs of putative TB susceptibility genes, as well as pairs of genes that have been curated in online databases as potential interactors, we use statistical modelling to identify pairs of interacting SNPs. We attempt to validate the top models identified in our discovery data set using an independent genome-wide TB case-control data set from The Gambia. A number of models were successfully validated, indicating that interplay between the NRG1 - NRG3, GRIK1 - GRIK3 and IL23R - ATG4C gene pairs may modify susceptibility to TB. Gene pairs involved in the NF-κB pathway were also identified in the discovery data set (SFTPD - NOD2, ISG15 - TLR8 and NLRC5 - IL12RB1), but could not be tested in the Gambian study group due to lack of overlapping data.
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    A panel of ancestry informative markers for the complex five-way admixed South African Coloured population
    (PLoS, 2013-12) Daya, Michelle; Van der Merwe, Lize; Ushma Galal; Möller, Marlo; Salie, Muneeb; Chimusa, Emile R.; Galanter, Joshua M.; Van Helden, Paul D.; Henn, Brenna M.; Gignoux, Chris R.; Hoal, Eileen
    Admixture is a well known confounder in genetic association studies. If genome-wide data is not available, as would be the case for candidate gene studies, ancestry informative markers (AIMs) are required in order to adjust for admixture. The predominant population group in the Western Cape, South Africa, is the admixed group known as the South African Coloured (SAC). A small set of AIMs that is optimized to distinguish between the five source populations of this population (African San, African non-San, European, South Asian, and East Asian) will enable researchers to cost-effectively reduce falsepositive findings resulting from ignoring admixture in genetic association studies of the population. Using genome-wide data to find SNPs with large allele frequency differences between the source populations of the SAC, as quantified by Rosenberg et. al’s In-statistic, we developed a panel of AIMs by experimenting with various selection strategies. Subsets of different sizes were evaluated by measuring the correlation between ancestry proportions estimated by each AIM subset with ancestry proportions estimated using genome-wide data. We show that a panel of 96 AIMs can be used to assess ancestry proportions and to adjust for the confounding effect of the complex five-way admixture that occurred in the South African Coloured population.
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    TLR1, 2, 4, 6 and 9 variants associated with tuberculosis susceptibility: a systematic review and meta-analysis
    (PLoS ONE, 2015) Schurz, Haiko; Daya, Michelle; Moller, Marlo; Hoal, Eileen G.; Salie, Muneeb
    Background: Studies investigating the influence of toll-like receptor (TLR) polymorphisms and tuberculosis susceptibility have yielded varying and often contradictory results in different ethnic groups. A meta-analysis was conducted to investigate the relationship between TLR variants and susceptibility to tuberculosis, both across and within specific ethnic groups. Methods: An extensive database search was performed for studies investigating the relationship between TLR and tuberculosis (TB) susceptibility. Data was subsequently extracted from included studies and statistically analysed. Results: 32 articles involving 18907 individuals were included in this meta-analysis, and data was extracted for 14 TLR polymorphisms. Various genetic models were employed. An increased risk of TB was found for individuals with the TLR2 rs3804100 CC and the TLR9 rs352139 GA and GG genotypes, while decreased risk was identified for those with the AG genotype of TLR1 rs4833095. The T allele of TLR6 rs5743810 conferred protection across all ethnic groups. TLR2 rs5743708 subgroup analysis identified the A allele to increase susceptibility to TB in the Asian ethnic group, while conferring protection in the Hispanic group. The T allele of TLR4 rs4986791 was also found to increase the risk of TB in the Asian subgroup. All other TLR gene variants investigated were not found to be associated with TB in this meta-analysis. Discussion: Although general associations were identified, most TLR variants showed no significant association with TB, indicating that additional studies investigating a wider range of pattern recognition receptors is required to gain a better understanding of this complex disease
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    Using bioinformatics and biostatistics to elucidate susceptibility to tuberculosis in an admixed population
    (Stellenbosch : Stellenbosch University, 2015-03) Daya, Michelle; Hoal, Eileen; Van der Merwe, Lize; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences: Molecular Biology and Human Genetics
    ENGLISH ABSTRACT : Tuberculosis is the second leading cause of mortality from infectious disease worldwide. One of the factors involved in developing disease is the genetics of the host, yet the field of TB susceptibility genetics has not yielded the insights that were expected. The admixed South African Coloured population is the largest demographic in metropolitan areas of Cape Town that have some of the highest reported incidences of TB worldwide. The DST/NRF Centre for Biomedical TB Research at Stellenbosch University has studied a cohort of individuals from these communities for many years, in the hope of discovering novel TB susceptibility genes which may at least partly explain the exceptional rate of TB in this community. The large genotypic data sets collected by the centre are invaluable resources to aid understanding of the population genetics of the population, and to generate new hypotheses regarding genetic factors that may underpin progression to disease. Novel applications of statistical methods are used in this dissertation with a view to addressing these goals, and are presented in four research studies. An important consideration in genetic association studies of the South African Coloured population is admixture, which may confound association results. This is the subject of the first two studies. The first study describes the development of a panel of ancestry informative markers that are tailored to the complex admixture that occurred in the population. The panel can be used as a cost-effective alternative to genome-wide data to correct for the confounding effect of admixture. In the second study, the panel is used to demonstrate the importance of adjustment for ancestry in TB susceptibility genetic association studies of the South African Coloured population. A previous study identified associations between ancestry and having TB in the population, but a limited number of controls were used in that study. Ancestry informative markers were therefore used to examine the previous finding, and the substantial effect that ancestry has in the development of TB was confirmed. New hypotheses regarding genetic factors in TB susceptibility are generated in the third and fourth studies. The South African Coloured population received contributions from diverse source populations that may differ in their genetic susceptibility to TB, and the group is therefore ideally suited to the discovery of TB susceptibility genetic variants and their probable ethnic origins. Genome-wide admixture mapping was used in the third study to identify regions of the genome that may harbour such variants. The study identified a number of novel candidate TB susceptibility genes, and provided further substantiating evidence for the role of genetic loci previously implicated in the disease. The fourth study investigated the role of gene-gene interactions (epistasis), an oft-cited explanation for the missing heritability of complex disease, in the South African Coloured TB case-control cohort. A number of interesting gene-gene pairs that may jointly modify the odds of having TB were identified, and some of these findings were validated in an independent TB case-control cohort from The Gambia.
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    Using multi-way admixture mapping to elucidate TB susceptibility in the South African Coloured population
    (BioMed Central, 2014-11) Daya, Michelle; Van der Merwe, Lize; Gignoux, Christopher R.; Van Helden, Paul D.; Moller, Marlo; Hoal, Eileen G.
    Background: The admixed South African Coloured population is ideally suited to the discovery of tuberculosis susceptibility genetic variants and their probable ethnic origins, but previous attempts at finding such variants using genome-wide admixture mapping were hampered by the inaccuracy of local ancestry inference. In this study, we infer local ancestry using the novel algorithm implemented in RFMix, with the emphasis on identifying regions of excess San or Bantu ancestry, which we hypothesize may harbour TB susceptibility genes. Results Using simulated data, we demonstrate reasonable accuracy of local ancestry inference by RFMix, with a tendency towards miss-calling San ancestry as Bantu. Regions with either excess San ancestry or excess African (San or Bantu) ancestry are less likely to be affected by this bias, and we therefore proceeded to identify such regions, found in cases but not in controls (642 cases and 91 controls). A number of promising regions were found (overall p-values of 7.19×10-5 for San ancestry and <2.00×10-16 for African ancestry), including chromosomes 15q15 and 17q22, which are close to genomic regions previously implicated in TB. Promising immune-related susceptibility genes such as the GADD45A, OSM and B7-H5 genes are also harboured in the identified regions. Conclusion Admixture mapping is feasible in the South African Coloured population and a number of novel TB susceptibility genomic regions were uncovered.