Using bioinformatics and biostatistics to elucidate susceptibility to tuberculosis in an admixed population
Daya, Michelle (2015-03)
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.
AFRIKAANSE OPSOMMING : Tuberkulose (TB) is wêreldwyd die tweede grootste oorsaak van sterftes weens aansteeklike siektes . Een van die faktore wat betrokke is by die ontwikkeling van die siekte is die genetika van die gasheer, maar die studie van genetiese vatbaarheid vir TB het nog nie voldoende antwoorde opgelewer nie. Die Suid-Afrikaanse Kleurlinge is die grootste bevolkingsgroep in stedelike gebiede van Kaapstad met van die hoogste voorkoms van TB wêreldwyd. Die DST/NRF Sentrum vir Biomediese TB-navorsing aan die Universiteit van Stellenbosch het oor baie jare ’n groep individue uit hierdie gemeenskappe gewerf en bestudeer, met die doel om nuwe TB-vatbaarheidgene te ontdek om die buitengewone voorkoms van TB in die gemeenskap te verklaar. Die groot genotipiese datastelle wat deur die sentrum ingesamel is, is belangrike hulpbronne om die bevolkingsgroep se genetiese samestelling beter te verstaan, en om nuwe hipoteses te skep rakende genetiese faktore wat oorskakeling na siekte kan bewerkstellig. Nuwe toepassings van bestaande statistiese metodes is gebruik om hierdie doelwitte teweeg te bring, en word as vier studies in die verhandeling aangebied. ’n Belangrike oorweging in studies van die genetiese verband met siekte in die Suid-Afrikaanse Kleurling bevolkingsgroep, is die vermenging van herkoms, wat resultate van genetiese studies kan beïnvloed. Dit is die onderwerp van die eerste twee studies. Die eerste studie beskryf die ontwikkeling van ’n paneel van genetiese merkers, wat die herkoms van hierdie bevolkingsgroep beskryf. Die paneel kan gebruik word as ’n koste-effektiewe alternatief tot genoom-wye data om statistiese modelle aan te pas vir die teenwoordigheid van verskillende bevolkingsgroepe in mense se herkoms. Die paneel word in die tweede studie gebruik om die belangrikheid van sodanige aanpassings te demonstreer. ’n Vorige studie het verbande tussen die kleurlinge se herkoms en vatbaarheid vir TB geïdentifiseer, maar ’n beperkte aantal kontrole-pasiënte is in daardie studie gebruik. Herkoms insiggewende merkers is gebruik om die vorige bevindings te ondersoek, en die aansienlike invloed wat herkoms het in die ontwikkeling van TB was bevestig. Nuwe hipoteses rakende genetiese faktore wat vatbaarheid vir TB beïnvloed, word in die derde en vierde studies geskep. Die Suid-Afrikaanse Kleurling bevolkingsgroep het genetiese bydraes van verskeie bevolkings ontvang, wat mag verskil in hul genetiese vatbaarheid vir TB. Die groep kan dus gebruik word om nuwe TB vatbaarheid genetiese variante en hul waarskynlike etniese oorsprong te ontdek. Kartering van genoom-wye herkoms-vermenging is in die derde studie gebruik om areas van die genoom te identifiseer wat moontlik sulke variante huisves. Die studie het ’n aantal nuwe kandidaat TB vatbaarheid gene geïdentifiseer, en ook areas van die genoom verneem as betrokke by TB bevestig. Die vierde studie ondersoek die rol van geengeen interaksies, ’n algemene verduideliking vir die onverklaarde oorerflikheid van komplekse siektes. ’n Aantal interessante geen-geen pare is geïdentifiseer, en ’n paar van hierdie bevindinge is bevestig in ’n groep van Die Gambië.
Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/96622
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Doctoral Degrees (Molecular Biology and Human Genetics)75