Investigation of genetic variation contributing to antipsychotic treatment response in a South African first episode schizophrenia cohort

[摘要] ENGLISH ABSTRACT: Schizophrenia is a debilitating disorder that occurs the world over. Although antipsychoticsare largely effective in treating the positive symptoms of schizophrenia, the outcomes arenon-optimal in many patients. As antipsychotic treatment response has been shown to beheritable, it is expected that the implementation of antipsychotic pharmacogenomics shouldaid in the optimization of antipsychotic treatments, however to date clinically applicableresults are limited. Therefore this study utilized exome sequencing in a cohort of wellcharacterized first episode schizophrenia patients to identify the genetic factorscontributing to antipsychotic treatment response.The utility of exome sequencing for antipsychotic pharmacogenomic applications in theAfrican context was assessed through examination of the literature and publically availabledata. Thereafter, a cohort of 104 well characterized South African first episodeschizophrenia patients who were treated with flupenthixol decanoate for twelve monthswas collected. From this cohort, subsets of patients on extreme ends of the treatmentresponse spectrum were identified for exome sequencing. Thereafter a bioinformaticspipeline was used to call and annotate variants. These variants and those that havepreviously been associated with antipsychotic response, along with a panel of ancestryinformative markers, were prioritized for genotyping in the entire cohort of patients. Aftergenotyping of the 393 variants, statistical analyses were performed to identify associationswith 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 ofthe genome may not be well suited to these technologies. Thus, it may be necessary tocombine exome sequencing with knowledge obtained from past research, as was done inthis 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 inantipsychotic treatment response and additionally detected 11 variants that weresignificantly associated with antipsychotic treatment response outcomes (P=2.19x10-5). Nineof 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 remainingtwo variants have been associated with antipsychotic treatment outcomes in previousGWAS. Examination of the function of the genes in which the variants occurred revealedthat the variants associated with (i) positive symptom improvement were involved in thefolate metabolism pathway and (ii) negative and general pathological symptomsimprovement had potential links to neuronal development and migration.To our knowledge this study is the first to utilize exome sequencing for antipsychoticpharmacogenomic purposes. The ability of this study to identify significant associations,even after correction for multiple testing, has highlighted the importance of combininggenomic technologies with well characterized cohorts. The results generated from this studyhave served both to replicate results from previous antipsychotic pharmacogenetic studiesand to identify novel genes and pathways involved in antipsychotic response. These resultsshould aid in improving our understanding of the biological underpinnings of antipsychotictreatment response and may ultimately aid in the optimization of these treatments.

[发布机构] Stellenbosch University