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Admixture mapping of TB susceptibility and the contribution of type 2 diabetes in a South African population
Thesis (PhD)--Stellenbosch University, 2022.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2022
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| _version_ | 1867613795311943680 |
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| access_status_str | Open Access |
| author | Swart, Yolandi |
| author2 | Moller, Marlo |
| author_browse | Moller, Marlo Swart, Yolandi |
| author_facet | Moller, Marlo Swart, Yolandi |
| author_sort | Swart, Yolandi |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2022. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/126362 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:41:46.856Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2022 |
| publishDateRange | 2022 |
| publishDateSort | 2022 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/126362 Admixture mapping of TB susceptibility and the contribution of type 2 diabetes in a South African population Swart, Yolandi Moller, Marlo Uren, Caitlin Kleynhans, Leanie Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics. Population genetics -- South Africa Human genetics -- South Africa Mycobacterium tuberculosis -- South Africa Type 2 diabetes -- South Africa UCTD Thesis (PhD)--Stellenbosch University, 2022. ENGLISH SUMMARY: Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), co-evolved with humans throughout known history. TB is still an ongoing global health threat and the development of TB is complex depended on multiple factors. Although it was established host genetic factors may play a role in developing active TB, study results mostly differed between ancestry groups. Apart from a severe lack of representation of genomic samples from Sub-Saharan Africa, it is also one of the highest TB burden regions worldwide. In addition, other factors such as type 2 diabetes (T2D) are rising at alarming rates on the African continent due to globalization and Westernised lifestyles. The challenge, however, in sub-Saharan African populations is to account for the vast levels of genetic diversity observed, and in some cases extending to a five-way admixed scenario. Besides the continuous overrepresentation of individuals of European descent in genetic research, the methods and available software tools used in genetic research are developed under the assumptions that individuals are homogenous (Chapter 1). Even though multiple studies inferred ancestry in admixed individuals to elucidate demographic history of a particular region, the frequent lack of admixture-specific methods lead to admixed populations often being excluded from these studies (Chapter 1). Nonetheless, correctly adjusting for population substructure in genetic association studies may lead to the identification of novel ancestry-specific genetic loci associated with a variety of phenotypes. To account for this genetic heterogeneity amongst South African admixed individuals in this thesis, we incorporated local ancestry as the number of inherited alleles (0,1 and/or 2) from each ancestral population (Chapter 2). With the use of additional models (Local Ancestry Allelic Association (LAAA) model), we were able to identify additional African-specific genetic variants associated with TB susceptibility in a five-way admixed South African population. To expand on the application of the LAAA model, simulation studies were conducted to test if the LAAA model will be able to capture the true causal variants when faced with any admixture scenario (Chapter 3). Our results indicated that one should not rely on one genome-wide association (GWAS) model to capture true causal variants. Furthermore, the inclusion of an interaction between the allele (major or minor) and ancestry present at each genomic loci along the genome of an admixed individual are recommended in statistical analysis (Chapters 2 and 3). Finally, cis-eQTL mapping was conducted to close the gap between GWAS and the clinical implementation of genetics in a TB-T2D cohort from South Africa (Chapter 4). Additionally, local ancestry was incorporated in cis-eQTL mapping analysis and enabled us to narrow down a list of most probable ancestry-specific genetic variants influencing the development of TB in T2D patients and healthy controls. Previously identified biological pathways implicated in both TB and T2D were identified and linked with a corresponding ancestry. We conclude with an overview of the findings in this thesis and recommend directions for future research. Including populations of complex ancestry and admixture is challenging but will become necessary to improve the quality of research in sub-Saharan African groups. AFRIKAANSE OPSOMMING: Tuberkulose (TB), veroorsaak deur die bakterium Mycobacterium tuberculosis (M.tb), het saam met die mens ontwikkel deur die eeue en is nogsteeds ‘n wereldwye gesondheidsprobleem. Die ontwikkeling van TB is kompleks en afhanklik van verskeie faktore. Alhoewel dit voorheen vasgestel is dat gasheerfaktore kan bydra tot die ontwikkeling van TB, het resultate nie ooreengestem tussen populasies met verskillende herkoms nie. TB kom nogsteeds algemeen voor in Afrika suid van die Sahara, ‘n streek wat gekenmerk word deur ‘n gebrek aan genomies monsters. Ander faktore, soos tipe-2-diabetes (T2D), neem teen ‘n kommerwekkende tempo toe in Afrika as gevolg van globalisering en verswesterde leefstyl. Populasies in Afrika het egter ‘n groot verskeindenheid genetiese diversiteit. Sommige populasies in Suid-Afrika het herkoms van tot vyf populasies wereldwyd ontvang en het gelei tot genetiese vermenging. In samehang met die oorverteenwoordiging van individue met Europese herkoms in genetise navorsing, word die sagteware en metodes ontwikkel onder die aannames dat individue homogeen is (Hoofstuk1). Die gebruik van herkoms in statistiese modelle was om die demografiese geskiedenis van ‘n streek te ontbloot en nie om genetiese variante te identifiseer vir mediese doeleindes nie. Populasies met gemengde herkoms word dikwels uitgesluit in genetiese navorsing en lei gevolglik tot die gebrek aan ontwikkeling van statistiese metodes (Hoofstuk 1). As herkoms wel korrek geinkorporeer kan word in genetiese assosiasiestudies, kan dit lei tot die identifikasie van nuwe herkoms-spesifieke genetiese variante wat assosieer met verskeie fenotipes. Geneties herkoms word in hierdie proefskrif ingesluit as die aantal oorgeerfde allele (0, 1 en/of 2) vanaf elke voorvaderlike populasie (Hoofstuk 2). Ons was instaat om addisionele Afrika-spesifieke genetiese variante te identifiseer wat assosieer met TB vatbaarheid in ‘n populasie wat heroms ontvang het van vyf verskillende voorvaderlike populasies deur gebruik te maak van alternatiewe modelle (“Local Ancestry Allelic Association (LAAA) model”). Om uit te brei oor die toepassing van die “LAAA”-model, was simulasie studies uitgevoer om te toets of die “LAAA”-model in staat sal wees om die werklike oorsaaklike genetiese variante vas te vang wanneer dit met enige vermengings scenario gekonfronteer word (Hooftsuk 3). Ons resultate het aangedui dat mens nie op enige genoom-wye assosiasiestudie (GWAS) model kan staatmaak om die werkilke oorsaaklike variante te identifiseer in gemengde populasies nie. Die interaksie tussen die alleel (groot of klein) en herkoms teenwoordig by elke genomiese lokus moet in ag geneem word in statiese modelle (Hoofstuk 2 en 3). Laastens, was cis-kartering uitgevoer om die gaping tussen GWAS en die kliniese implementering van genetika in ‘n TB-T2D-kohort van Suid-Afrika te verminder (Hoofstuk 4). Die plaaslike herkoms was geinkorporeer in die cis-kartering analises en ‘n lys van mees warskynlike herkoms-spesifieke genetiese variante wat lei tot die ontwikkeling van TB in T2D pasiente en gesonde individue, was geindentifiseer. Biologiese padwee wat voorheen geimpliseer was met TB en T2D was dus gekoppel met herkoms. Ons sluit af met ‘n oorsig van die bevindinge in hierdie proefskrif en aanbevelings vir toekomstige navorsing. Die insluiting van bevolkings met komplekse herkoms in genetiese assosiasiestudies is uitdagend, maar word benodig om die gehalte van navorsing in sub-Sahara Afrika-groepe te verbeter. Doctoral 2022-11-21T09:37:57Z 2023-01-23T06:54:06Z 2022-11-21T09:37:57Z 2022-12 Thesis http://hdl.handle.net/10019.1/126362 en_ZA Stellenbosch University 183 pages : illustrations, maps application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Population genetics -- South Africa Human genetics -- South Africa Mycobacterium tuberculosis -- South Africa Type 2 diabetes -- South Africa UCTD Swart, Yolandi Admixture mapping of TB susceptibility and the contribution of type 2 diabetes in a South African population |
| title | Admixture mapping of TB susceptibility and the contribution of type 2 diabetes in a South African population |
| title_full | Admixture mapping of TB susceptibility and the contribution of type 2 diabetes in a South African population |
| title_fullStr | Admixture mapping of TB susceptibility and the contribution of type 2 diabetes in a South African population |
| title_full_unstemmed | Admixture mapping of TB susceptibility and the contribution of type 2 diabetes in a South African population |
| title_short | Admixture mapping of TB susceptibility and the contribution of type 2 diabetes in a South African population |
| title_sort | admixture mapping of tb susceptibility and the contribution of type 2 diabetes in a south african population |
| topic | Population genetics -- South Africa Human genetics -- South Africa Mycobacterium tuberculosis -- South Africa Type 2 diabetes -- South Africa UCTD |
| url | http://hdl.handle.net/10019.1/126362 |
| work_keys_str_mv | AT swartyolandi admixturemappingoftbsusceptibilityandthecontributionoftype2diabetesinasouthafricanpopulation |