Browsing by Author "Schurz, Haiko"

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    Evaluating the accuracy of imputation methods in a five-way admixed population
    (Frontiers Media, 2019) Schurz, Haiko; Muller, Stephanie J.; Van Helden, Paul David; Tromp, Gerard; Hoal, Eileen G.; Kinnear, Craig J.; Moller, Marlo
    Genotype imputation is a powerful tool for increasing statistical power in an association analysis. Meta-analysis of multiple study datasets also requires a substantial overlap of SNPs for a successful association analysis, which can be achieved by imputation. Quality of imputed datasets is largely dependent on the software used, as well as the reference populations chosen. The accuracy of imputation of available reference populations has not been tested for the five-way admixed South African Colored (SAC) population. In this study, imputation results obtained using three freely-accessible methods were evaluated for accuracy and quality. We show that the African Genome Resource is the best reference panel for imputation of missing genotypes in samples from the SAC population, implemented via the freely accessible Sanger Imputation Server.
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    IMPUTOR : phylogenetically aware software for imputation of errors in next-generation sequencing
    (Oxford University Press, 2018) Jobin, Matthew; Schurz, Haiko; Henn, Brenna M.
    ENGLISH ABSTRACT: We introduce IMPUTOR, software for phylogenetically aware imputation of missing haploid nonrecombining genomic data. Targeted for next-generation sequencing data, IMPUTOR uses the principle of parsimony to impute data marked as missing due to low coverage.Alongwith efficiently imputingmissing variant genotypes, IMPUTOR is capable of reliably and accurately correcting manynonmissingsites that represent spurious sequencing errors. Testsonsimulateddata showthatIMPUTORis capable of detecting many induced mutations without making erroneous imputations/corrections, with as many as 95% of missing sites imputed and 81%of errors corrected under optimal conditions.We tested IMPUTOR with human Y-chromosomes from pairs of close relatives and demonstrate IMPUTOR’s efficacy in imputing missing and correcting erroneous calls.
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    Sex-bias and tuberculosis susceptibility: Bioinformatic and Biostatistical evaluation of trans-ethnic genomic datasets
    (Stellenbosch : Stellenbosch University, 2018-12) Schurz, Haiko; Moller, Marlo; Hoal, Eileen; Tromp, Gerard; Kinnear, Craig; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences: Molecular Biology and Human Genetics.
    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.
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    A sex-stratified genome-wide association study of tuberculosis using a multi-ethnic genotyping array
    (Frontiers Media, 2019) Schurz, Haiko; Kinnear, Craig J.; Gignoux, Chris; Wojcik, Genevieve; Van Helden, Paul D.; Tromp, Gerard; Henn, Brenna; Hoal, Eileen G.; Moller, Marlo
    Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a complex disease with a known human genetic component. Males seem to be more affected than females and in most countries the TB notification rate is twice as high in males than in females. While socio-economic status, behavior and sex hormones influence the male bias they do not fully account for it. Males have only one copy of the X chromosome, while diploid females are subject to X chromosome inactivation. In addition, the X chromosome codes for many immune-related genes, supporting the hypothesis that X-linked genes could contribute to TB susceptibility in a sex-biased manner. We report the first TB susceptibility genome-wide association study (GWAS) with a specific focus on sex-stratified autosomal analysis and the X chromosome. A total of 810 individuals (410 cases and 405 controls) from an admixed South African population were genotyped using the Illumina Multi Ethnic Genotyping Array, specifically designed as a suitable platform for diverse and admixed populations. Association testing was done on the autosome (8,27,386 variants) and X chromosome (20,939 variants) in a sex stratified and combined manner. SNP association testing was not statistically significant using a stringent cut-off for significance but revealed likely candidate genes that warrant further investigation. A genome wide interaction analysis detected 16 significant interactions. Finally, the results highlight the importance of sex-stratified analysis as strong sex-specific effects were identified on both the autosome and X chromosome.
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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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    The X chromosome and sex-specific effects in infectious disease susceptibility
    (BMC (part of Springer Nature), 2019-01-08) Schurz, Haiko; Salie, Muneeb; Tromp, Gerard; Hoal, Eileen G.; Kinnear, Craig J.; Moller, Marlo
    ENGLISH ABSTRACT: The X chromosome and X-linked variants have largely been ignored in genome-wide and candidate association studies of infectious diseases due to the complexity of statistical analysis of the X chromosome. This exclusion is significant, since the X chromosome contains a high density of immune-related genes and regulatory elements that are extensively involved in both the innate and adaptive immune responses. Many diseases present with a clear sex bias, and apart from the influence of sex hormones and socioeconomic and behavioural factors, the X chromosome, X-linked genes and X chromosome inactivation mechanisms contribute to this difference. Females are functional mosaics for X-linked genes due to X chromosome inactivation and this, combined with other X chromosome inactivation mechanisms such as genes that escape silencing and skewed inactivation, could contribute to an immunological advantage for females in many infections. In this review, we discuss the involvement of the X chromosome and X inactivation in immunity and address its role in sexual dimorphism of infectious diseases using tuberculosis susceptibility as an example, in which male sex bias is clear, yet not fully explored.