Browsing by Author "Jooste, Sarel Christiaan"
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- ItemCharacterising the epigenetic architecture of differential treatment outcomes in a South African first-episode schizophrenia cohort with emphasis on miRNA-mediated regulation(Stellenbosch : Stellenbosch University, 2023-12) Jooste, Sarel Christiaan; Mcgregor, Nathaniel Wade; Pearce, Brendon; Stellenbosch University. Faculty of Agrisciences. Dept. of Genetics.ENGLISH ABSTRACT: Approximately 24 million individuals of the global population are affected by schizophrenia. Strikingly, antipsychotic treatment remains effective in only half of these individuals. This is a product of the complex multifactorial nature of the disorder and even more so its treatment. It has become a necessity to utilize the genetic and neurological underpinnings of the disorder, to elucidate and potentially improve on actionable clinical treatments, such as an improved susceptibility risk estimates and point-of-care diagnosis detection devices. Genome-Wide Association studies provide remarkable insights into the heritable component of neuropsychiatric disorders, although they still only explains a part of the presentation of the disorder. Variations in neuronal structure, as well as other environmental and epigenetic influences critically contribute to the interplay between the aetiology and treatment of schizophrenia. The hyper-focus on the direct genomic structure alone is perhaps due for re-evaluation into potential biomarkers that may play a more regulatory role, such as the cascade of epigenetic effects of miRNA. Biomarkers, briefly defined as a DNA sequence associated to the susceptibility of a biological risk, may also be directly measurable and may lead to greater insights into the missing heritability of the pharmacogenetics of antipsychotic medication. This study primarily focused on miRNAs to identify potential biomarkers for neuropsychiatric disorders and specifically differential antipsychotic treatment responses. A special focus was placed on hsa-miR-548al, a miRNA which has previously been implicated in the pathophysiology of schizophrenia and treatment thereof. For the purposes of this study, a particular single nucleotide polymorphism, rs515924, in the seed sequence of the focal miRNA was specifically investigated. The study utilizes 103 first-episode schizophrenia patients treated with long-acting injectable flupentixol decanoate, as well as mixed- ancestry genome wide association studies data from schizophrenic individuals. Candidate genes that are influenced by the target miRNA were identified. Finally, mixed-effects linear regression and logistic regression association analyses were performed to assess the statistical significance of the miRNA’s impact on differential treatment responses in schizophrenia. The results shows clear trends towards nominal significance (p-value < 0.05) for the miRNA SNP hsa-miR-548al rs515924, as well as for candidate SNPs found in genes predicted to be affected by hsa-miR-548al to be associated with differential antipsychotic treatment responses. These associations were found to be modified when including the severity of childhood trauma as an interacting variable. The dysregulation of hsa-miR- 548al or its target genes may impact molecular pathways related to differential treatment outcomes, such as the neuronal developmental pathways and immune pathways, highlighting the importance of miRNA-mediated gene regulation. The findings suggest that rs515924 could serve as a predictive marker for treatment response and inform tailored treatment approaches. This research contributes to filling the knowledge gap in understanding the complex interplay between genetic and epigenetic variations and clinical phenotypes in differential antipsychotic treatment response.