Browsing by Author "Prinsloo, Hendrik Johannes"
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- ItemAn integrative data-analysis of miRNA-related contributions to the pathophysiology of neuropsychiatric disorders(Stellenbosch : Stellenbosch University, 2022-12) Prinsloo, Hendrik Johannes; McGregor, Nathaniel W.; Stellenbosch University. Faculty of AgriSciences. Dept. of Genetics.ENGLISH ABSTRACT: The detrimental burden of disease brought on by neuropsychiatric disorders (NDs) continues to hinder societal and personal growth, especially in developing countries where antipsychotic treatment is inadequate. Additionally, antipsychotic treatment is lacking in effectiveness and the discrepancy between population groups in medical research is potentially contributing to poorer antipsychotic treatment response (ATR) in understudied populations. Despite the ever-growing list of potential biomarkers for complex disease, the field of psychiatry has seen little clinical improvement in both diagnosis and ATR. Recently, micro-RNA (miRNA) has become a potential leading epigenetic watchdog for ND aetiology due to high expression rates in the mammalian brain and could potentially, through the synaptic plasticity pathway, influence ATR. This assumption arises from the connection between environmental change, miRNA gene regulation, and neuroadaptation. In this regard, synaptic plasticity genes have previously been heavily implicated in ND aetiology and some miRNA have also found significance, and even GWAS significance, in disorders such as schizophrenia (SCZ). Despite this, little is known about the intricate network between miRNA and ATR. Variation in miRNA-target interactions could provide much needed insight into differential ATR which in turn leads to adverse drug reactions. The present study aims to characterise miRNA binding variation within synaptic plasticity genes to inform on differential treatment outcome. Additionally, due to the unique admixture of the South African cohort used in this study, the involvement of ancestry is also explored in the context of ATR. The South African cohort comprised of 103 drug naïve first episode schizophrenia (FES) patients, all treated with the same antipsychotic in the form of a long acting injectable, flupenthixol decanoate. Subsequently, psychotic symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) over a 12-month period. Candidate genes in the synaptic plasticity pathway were used to initiate a bioinformatic pipeline to identify genetic variants at miRNA binding sites which were subsequently tested for ATR association with linear regression and mixed-effects modelling. This resulted in a list of six SNPs with significant association in respective symptom domains. Specifically of interest was the association between rs635903 and the negative symptom domain alone, as well as rs3735666 and its strong association with both the total and negative symptom domain. Both these SNPs led to differential miRNA binding sequences on their respective mRNAs, leading to change in repression strength and consequently differential ATR. Additionally, significant SNPs were used to cluster response group and more responsive cases showed clear bias towards European ancestry. Furthermore, less responsive individuals tended to score high in African San ancestry. This further reinforces the claim that the Eurocentric focus of medical research leads to poor response in underrepresented populations. The present study thus elucidates the role of miRNA binding variation in ATR and showcases the importance of including mixed ancestry populations in medical research to improve on treatment outcome. The consideration of these aspects could lead to the development of more effective means of diagnosing and treating disorders such as SCZ.