Doctoral Degrees (Molecular Biology and Human Genetics)

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Browsing Doctoral Degrees (Molecular Biology and Human Genetics) by Subject "Antipsychotics"

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    Investigation of genetic variation contributing to antipsychotic treatment response in a South African first episode schizophrenia cohort
    (Stellenbosch : Stellenbosch University, 2013-12) Drogemoller, Britt Ingrid; Warnich, L. ; Emsley, Robin; Niehaus, Dana; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biology and Human Genetics. Molecular Biology and Human Genetics.
    ENGLISH ABSTRACT: Schizophrenia is a debilitating disorder that occurs the world over. Although antipsychotics are largely effective in treating the positive symptoms of schizophrenia, the outcomes are non-optimal in many patients. As antipsychotic treatment response has been shown to be heritable, it is expected that the implementation of antipsychotic pharmacogenomics should aid in the optimization of antipsychotic treatments, however to date clinically applicable results are limited. Therefore this study utilized exome sequencing in a cohort of well characterized first episode schizophrenia patients to identify the genetic factors contributing to antipsychotic treatment response. The utility of exome sequencing for antipsychotic pharmacogenomic applications in the African context was assessed through examination of the literature and publically available data. Thereafter, a cohort of 104 well characterized South African first episode schizophrenia patients who were treated with flupenthixol decanoate for twelve months was collected. From this cohort, subsets of patients on extreme ends of the treatment response spectrum were identified for exome sequencing. Thereafter a bioinformatics pipeline was used to call and annotate variants. These variants and those that have previously been associated with antipsychotic response, along with a panel of ancestry informative markers, were prioritized for genotyping in the entire cohort of patients. After genotyping of the 393 variants, statistical analyses were performed to identify associations with treatment response outcomes. Examination of the literature revealed a need for exome sequencing in Africa. However, critical analyses of next generation sequencing data demonstrated that complex regions of the genome may not be well suited to these technologies. Thus, it may be necessary to combine exome sequencing with knowledge obtained from past research, as was done in this study to identify the genetic factors contributing to antipsychotic treatment response. Using this strategy, the current study highlighted the potential role that rare variants play in antipsychotic treatment response and additionally detected 11 variants that were significantly associated with antipsychotic treatment response outcomes (P=2.19x10-5). Nine of these variants were predicted to alter the function of the genes in which they occurred; of which eight were novel with regards to antipsychotic treatment response. The remaining two variants have been associated with antipsychotic treatment outcomes in previous GWAS. Examination of the function of the genes in which the variants occurred revealed that the variants associated with (i) positive symptom improvement were involved in the folate metabolism pathway and (ii) negative and general pathological symptoms improvement had potential links to neuronal development and migration. To our knowledge this study is the first to utilize exome sequencing for antipsychotic pharmacogenomic purposes. The ability of this study to identify significant associations, even after correction for multiple testing, has highlighted the importance of combining genomic technologies with well characterized cohorts. The results generated from this study have served both to replicate results from previous antipsychotic pharmacogenetic studies and to identify novel genes and pathways involved in antipsychotic response. These results should aid in improving our understanding of the biological underpinnings of antipsychotic treatment response and may ultimately aid in the optimization of these treatments.