Browsing by Author "Ovenden, Ellen Susan"
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- ItemInvestigating the functional significance of genome-wide variants associated with antipsychotic treatment response in schizophrenia(Stellenbosch : Stellenbosch University, 2015-12) Ovenden, Ellen Susan; Warnich, L. ; Emsley, Robin; Stellenbosch University. Faculty of AgriSciences. Dept. of Genetics.ENGLISH ABSTRACT: Schizophrenia is a debilitating disease affecting approximately 70 million people worldwide. Response to treatment, much like the disorder itself, is highly heritable, heterogeneous, and poorly understood. Only 50% of patients respond well to medication, and extensive research has provided limited improvement on this figure. Advances in genetic technologies coupled with massive increases in study sample size have the potential to explain the “missing heritability” of both schizophrenia and treatment response. Genome-wide association studies (GWAS) are at the forefront of complex trait research, but have had minimal success in terms of explaining the biology of psychiatric drug response. Despite the majority of GWAS “hits” being located in noncoding regions, functional interpretation is usually restricted to the closest gene. The Encyclopedia of DNA Elements (ENCODE) project has recently shown that noncoding variation is not just a functional proxy of adjacent coding regions, but can have complex and pervasive regulatory effects. This study aimed to investigate the functionality of noncoding single nucleotide polymorphisms (SNPs) in schizophrenia treatment response. A novel bioinformatics pipeline incorporated coding and noncoding variants implicated in treatment response, regions of linkage disequilibrium (LD), regulatory data, and biological pathway predictions. Firstly, the literature was mined to identify all variants associated via GWAS with antipsychotic response, after which publically available data was employed to find markers in LD with these variants. This larger group of variants was analysed with bioinformatic tools such as RegulomeDB and rSNPBase to determine regulatory potential. Thereafter, affected gene targets and pathways were identified with DAVID and GeneMANIA. In order to investigate the findings further, the top predicted regulatory variants and their GWAS partners were genotyped with TaqMan® OpenArray® in a South African first episode schizophrenia (FES) cohort and analysed for associations with treatment outcomes. The bioinformatic portion of this study implicated a region on chromosome 4q24 associated with treatment-refractory schizophrenia through involvement of the nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1) gene. This gene is a master regulator involved in immunity and has over 200 gene targets. NFKB1 and immune dysregulation have both previously been implicated in schizophrenia, pointing to a genetic overlap between schizophrenia risk and antipsychotic treatment response. The most significant variants in the association analyses occurred at the 4q24 locus, with rs230493 and rs3774959 significantly associated with poor response in the negative symptom domain (P < 0.0001). These findings suggest a genetic link between persistent negative symptoms and treatment nonresponse. Additionally, a 14-variant haplotype containing these two polymorphisms was associated with 4.41% higher positive symptom severity. Not only do these results validate the importance of the 4q24 region in antipsychotic response, but they emphasise the overlap of schizophrenia risk and drug response, and the potential role of genomic dysregulation in undesirable treatment outcomes. NFKB1 and other associated genes should be studied in population-specific, replicative cohorts, in order to validate potential biomarkers of treatment response. This study illustrated the importance of thorough GWAS interpretation and inclusion of coding and noncoding variants to form biological hypotheses and better understand antipsychotic response.