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

Drogemoller, Britt Ingrid (2013-12)

Thesis (PhD)--Stellenbosch University, 2013.

Thesis

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.

AFRIKAANSE OPSOMMING: Skisofrenie is ‘n siekte wat wêreldwyd voorkom en lei tot erge funksionele inkorting. Alhoewel antipsigotiese medikasie redelik effektief is in die behandeling van die positiewe simptome van skisofrenie, is die funksionele uitkomste in baie pasiënte nie optimaal nie. Die reaksie op antipsigotiese behandeling blyk oorerflik te wees. Die verwagting is dus dat die implementering van antipsigotiese farmakogenomika met die optimalisering van antipsigotiese behandeling sal help. Tot dusver het die resultate van farmakogenomika studies egter beperkte kliniese toepassings opgelewer. Hierdie studie het dus eksoomvolgordebepaling in 'n groep van goed-karakteriseerde eerste-episode skisofrenie pasiënte gebruik om die genetiese faktore wat bydra tot die antipsigotiese behandelings-reaksies te identifiseer. Die gebruik van eksoom-volgordebepaling vir antipsigotiese farmakogenomika in die Afrikakonteks is deur die ondersoek van literatuur en openbaar-beskikbare data geëvalueer. Daarna is 'n groep van 104 goed-gekarakteriseerde Suid-Afrikaanse eerste-episode skisofrenie pasiënte, wat met flupenthixol dekanoaat vir twaalf maande behandel is, versamel. Uit hierdie groep is subgroepe van pasiënte op die teenoorgestelde eindpunte van die behandelings-reaksiespektrum vir eksoom-volgordebepaling geïdentifiseer. Hierna is 'n bioinformatika pyplyn gebruik om variante te identifiseer en te annoteer. Hierdie variante, asook variante wat voorheen met antipsigotiese reaksie geassosieer is, is saam met 'n paneel van afkoms-informatiewe merkers vir genotipering in die hele groep pasiënte geprioritiseer vir genotipering. Na genotipering van die 393 variante, is statistiese analises uitgevoer om assosiasies met behandelings-reaksie uitkomste te identifiseer. ‘n Ondersoek van die literatuur het getoon dat daar 'n behoefte vir eksoomvolgordebepaling in Afrika is. ‘n Kritiese analise van volgende-generasie volgordebepalings data het egter getoon dat komplekse dele van die genoom nie geskik is vir die gebruik van hierdie tegnologie nie. Om die genetiese faktore wat bydra tot suksesvolle antipsigotiese behandeling te identifiseer, mag dit nodig wees om eksoom-volgordebepaling te kombineer met bevindings verkry uit vorige navorsing, soos gedoen in hierdie studie. In die huidige studie het die gebruik van hierdie strategie die potensiële rol van skaars variante in antipsigotiese behandelings-reaksies beklemtoon en ‘n bykomende 11 variante is geïdentifiseer wat beduidend met antipsigotiese behandelingsrespons geassosieer is (P=2.19x10-5). Daar is voorspel dat nege van hierdie variante die funksie van die gene waarin hulle voorkom sal verander en agt van hierdie variante is vir die eerste keer met antipsigotiese behandelingsrespons geassosieer. Die oorblywende twee variante is met antipsigotiese behandelingsrespons in vorige GWAS geassosieer. ‘n Ondersoek na die funksie van die gene waarin die variasies voorgekom het, toon dat die variante wat geassosieer is met (i) verbetering van positiewe simptome ‘n rol speel in folaatmetabolisme, terwyl variante wat geassosieer is met (ii) die verbetering in negatiewe en algemene patologiese simptome potensiële skakels met neuron ontwikkeling en migrasie het. Na ons wete is hierdie die eerste studie wat eksoom-volgordebepaling vir antipsigotiese farmakogenomika doeleindes gebruik. Die vermoë van hierdie studie om beduidende assosiasies te identifiseer, selfs na korreksie vir veelvoudige toetse, onderstreep die belangrikheid van die kombinering van genomiese tegnologie met goed-gekarakteriseerde pasiënte. Die bevindinge van hierdie studie het nie net die resultate van vorige antipsigotiese farmakogenetiese studies bevestig nie, maar ook nuwe gene en variante wat betrokke is in antipsigotiese reaksie geïdentifiseer. Hierdie resultate sal hopelik ons begrip van die onderliggende biologiese faktore wat antipsigotiese behandelingsrespons beïnvloed verbeter en uiteindelik ook met die optimalisering van behandeling help.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/95473
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