Sex-bias and tuberculosis susceptibility: Bioinformatic and Biostatistical evaluation of trans-ethnic genomic datasets

Schurz, Haiko (2018-12)

Thesis (PhD)--Stellenbosch University, 2018.

Thesis

ENGLISH ABSTRACT: Approximately 25% of the world’s population is infected with Mycobacterium tuberculosis (M.tuberculosis). Progression to active tuberculosis (TB) is influenced by the infecting strain of M.tuberculosis, the environment and the genetic makeup of the host. Globally, the incidence rate for TB in males is nearly twice as high compared to females, indicating that biological sex of an individual also contributes to TB susceptibility. While environmental factors and sex hormones influence the immune system and affect the male bias, they do not fully account for it. This suggests that the X chromosome and the unique biology regulating X-linked gene expression in females could significantly influence progression to active TB. The X chromosome contains nearly 200 genes that are involved in the immune system. This clearly links the X chromosome to both the innate and humoral immune response and could explain why females have a more robust immune response against infections. X-linked genes have also been implicated in TB susceptibility, but these have not been conclusively linked to disease. Population specific effects could further contribute to the impact of the X chromosome on disease progression especially for populations that experienced sex-biased admixture. Here we investigated the five way admixed South African Coloured (SAC) population that has sexspecific genetic contributions from Bantu-speaking African, European, KhoeSan and South and East Asian populations. We showed that global ancestry inference could be used to detect the presence of sex-biased admixture and that this correlates with previous results indicating a KhoeSan female bias and a European and Bantu-speaking African male bias. We used SAC genome-wide association (GWAS) data and analysed the autosomes and X chromosome in a sex-stratified and combined manner, revealing sex-specific effects on both the autosome and X chromosome. A genome-wide interaction analysis also revealed significant interactions highlighting the need for epistatic and sex-stratified analysis in complex diseases. X chromosome data from the International Tuberculosis Host Genetic Consortium (ITHGC) was available to conduct a large trans-ethnic X-linked meta-analysis of TB susceptibility. The metaanalysis included imputed GWAS data from two Chinese, one Russian, a Ghanaian and Gambian and two SAC cohorts (23229 samples). We optimised imputation in our SAC data and showed that even diverse African populations can be imputed with great accuracy. The meta-analysis revealed novel X-linked genes associated with TB susceptibility. These genes were located in genomic regions on the X chromosome previously associated with TB susceptibility. Results from the meta-analysis also further confirmed the presence of both sex-specific and population specific effects. Our work highlights the importance of not only conducting sex-stratified analysis to elucidate sexspecific effects, but also to plan the study accordingly. Due to the strong impact of population specific effects, extremely large meta-analysis will be needed to fully elucidate global and population specific susceptibility variants. While the X chromosome has been mostly neglected in the past, tools for its analysis are now readily available. Our findings support the mandatory inclusion of the X chromosome in large-scale genetic studies.

AFRIKAANSE OPSOMMING: Ongeveer 25% van die wêreld se bevolking is geïnfekteer met Mikobacterium tuberculosis. Die ontwikkeling van aktiewe tuberkulose (TB) word beïnvloed deur die bakterium, die omgewing en die genetiese komponent van die gasheer. Die siekte tas twee keer soveel mans as vroue aan, wat aandui dat biologiese geslag ook bydra tot TB vatbaarheid. Alhoewel beide omgewingsfaktore en geslagshormone die immuunstelsel sowel as die TB geslagsvooroordeel beïnvloed, is dit nie ten volle daarvoor verantwoordelik nie. Dit dui daarop dat die X-chromosoom en die unieke biologie wat Xgekoppelde geenuitdrukking in vroue reguleer aansienlik kan bydra tot die ontwikkeling van aktiewe TB. Die X-chromosoom bevat byna 200 gene wat by die immuunstelsel betrokke is. Hierdie gene verbind die X-chromosoom aan beide die aangebore en humorale immuunrespons en kan verduidelik waarom vroue 'n sterker immuunrespons teen infeksies het. X-gekoppelde gene is ook betrek by TB vatbaarheid, maar dit is nie voldoende verbind aan die siekte nie. Bevolkingspesifieke effekte kan verder bydra tot die impak van die X-chromosoom op die ontwikkeling van die siekte, veral vir bevolkings waar genetiese vermenging met geslagsvooroordeel plaas gevind het. Hierdie tesis ondersoek Suid-Afrikaanse individue (SAC) wat geslags-spesifieke genetiese vermenging het van Bantoe-sprekende Afrikane-, Europese, KhoeSan- en Suid- en Oos-Asiatiese bevolkings. Ons wys dat globale vermenging inferensie gebruik kan word om die teenwoordigheid van geslagsvooroordeel te bepaal en dat dit korreleer met vorige resultate wat dui op 'n vroulike KhoeSan vooroordeel en 'n manlike Europese en Bantoe-sprekende Afrika vooroordeel. Ons gebruik SAC genoom-wye assosiasie (GWAS) data en ontleed die outosoom- en X-chromosoom op 'n geslags-gestratifiseerde en gekombineerde wyse, wat geslags-spesifieke effekte op beide die autosome en X-chromosoom openbaar. 'n Genoom-wye interaksie-analise het ook betekenisvolle interaksies aangedui wat die nut van epistatiese en geslags-gestratifiseerde analise in komplekse siektes beklemtoon. X chromosoom data van die Internasionale Tuberkulose gasheer genetiese konsortium (ITHGC) was beskikbaar om 'n groot transetniese X-gekoppelde meta-analise van TB-vatbaarheid uit te voer. Die meta-analise het toegepaste GWAS data van twee Chinese, een Russiese, 'n Ghanese en Gambiese en twee SAC versamelings (23229 monsters) ingesluit. Ons het toerekening in ons SAC-data optimiseer en toon dat selfs diverse Afrika-bevolkings met groot akkuraatheid toegereken kan word. Die meta-analise onthul nuwe X-gekoppelde gene wat verband hou met TB-vatbaarheid. Hierdie gene word gevind in genomiese streke op die X-chromosoom wat voorheen geassosieer is met TBvatbaarheid. Resultate van die meta-analise bevestig verder die teenwoordigheid van beide gespesifiseerde en populasie spesifieke effekte.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/105621
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