Browsing by Author "Coffee, Michelle"
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- ItemAnalysis of schizophrenia susceptibility variants identified by GWAS : a bioinformatics and molecular genetics approach(Stellenbosch : Stellenbosch University, 2014-12) Coffee, Michelle; Warnich, L. ; Niehaus, D. J. H.; Stellenbosch University. Faculty of AgriSciences. Dept. of Genetics.ENGLISH ABSTRACT: Described as one of the costliest and most debilitating disorders, schizophrenia has proven to be among the greatest challenges for medical researchers. The disorder poses difficulties on all levels: from genotype to phenotype. Even though it is known that there is a substantial genetic contribution to schizophrenia susceptibility (~80%), it is unknown whether this is due to common variants, rare variants, epigenetic factors, polymorphisms in regulatory regions of the genome or a combination of all these factors. Over the past few decades, many approaches have been employed to elucidate the genetic architecture of schizophrenia, with the latest and most promising being genome wide association studies (GWAS). However, nearly a decade after the first GWAS, the limitations are increasingly being recognised and new avenues need to be explored. Studies have recently started to focus on the analysis of non-coding regions of the genome since these regions harbour the majority of variants identified in GWAS thus far. This study aimed to use recently developed programs that utilize data from large scale studies such as previous GWAS, the Encyclopaedia of DNA Elements (ENCODE), 1000 Genomes, HapMap and Functional Annotation of the Mammalian Genome (FANTOM) to establish a simple, yet effective bioinformatics pipeline for the identification and assessment of variants in regulatory regions. Using the established workflow, 149 single nucleotide polymorphisms (SNPs) in regulatory regions were implicated in schizophrenia susceptibility, with the most significant SNP being rs200981. Pathway and network analysis using the Database for Annotation, Visualization and Integrated Discovery (DAVID) and GeneMANIA respectively indicated that the most frequently affected genes were involved in immune responses or neurodevelopmental processes, which support previous findings. Yet, novel findings of this study implicated processes crucial for DNA packaging (from DNA level to chromatin level). The second part of the study used restriction fragment length polymorphism analysis of polymerase chain reaction-amplified fragments (PCR-RFLP) to genotype ten of the most significant SNPs (identified by bioinformatic analyses in the first part of the study) in a South African Xhosa cohort of 100 cases and 100 controls, while bi-directional Sanger sequencing was used to confirm the presence of these SNPs. Statistical analyses revealed two haplotypes of regulatory variants, rs200483-rs200485-rs2517611 (p = 0.0385; OR = 1.71; 95% CI = 1.01-2.91) and rs200981-rs2517611-rs3129701 (p = 0.041; OR = 0.51; 95% CI = 0.27-0.98) associated with schizophrenia susceptibility. Bioinformatic analysis indicated that these haplotypes affect DNA packaging, which supported the findings of the first part of the study and could implicate epigenetic processes. The findings of this study support the importance of regulatory variants in schizophrenia susceptibility. This study also showed the importance of combining GWAS data with additional analyses in order to better understand complex diseases. It is hoped that these findings could fuel future research, specifically in genetically unique populations.