Browsing by Author "Newey, David Christopher"
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- ItemThe Potential Regulatory Role of microRNA in Methamphetamine Use Disorder (MUD)(Stellenbosch : Stellenbosch University, 2020-12) Newey, David Christopher; McGregor, Nathaniel W.; O'Connell, Kevin; Lochner, Christine; Stellenbosch University. Faculty of AgriSciences. Dept. of Genetics.ENGLISH ABSTRACT: Methamphetamine (MA) is a psychostimulant affecting the central nervous system. Individuals with methamphetamine use disorder (MUD) present compulsive substance-seeking behaviour and impaired control over use. Use of MA is associated with symptoms such as euphoria, hyperalertness and impairments in executive function and working memory. MA is a common substance of abuse in South Africa. MUD is a multifactorial psychiatric condition with its aetiology involving a complex interplay between genes and environmental factors. Evidence suggests that mechanisms regulating behavioural abnormalities associated with MUD involve changes in gene expression throughout the brain’s reward circuitry. Genome-wide association studies (GWAS) have revealed genes that may be involved in MUD. Additionally, a role has been established for epigenetic mechanisms, such as miRNA, mediating the effects of MA on the brain. There is an increase in studies investigating miRNA involvement in MUD. Considering links between environment, miRNA and neuropsychiatric disorders and the overlap in the molecular pathways of these disorders, it is likely that these pathways are regulated differently resulting in their differing clinical manifestations. Hence, this study aimed to elucidate the role of miRNA-mediated regulation in MUD and further disentangle the molecular underpinnings of MUD in a South African context. This was accomplished through a regression analysis of data from a local cohort with a diagnosis of MUD before performing in silico analyses on MUD data and a discovery cohort with cocaine use disorder (CUD); as both MA and cocaine are classed as psychostimulants. The MUD cohort was genotyped and imputed before being used in a regression analysis to identify single-nucleotide polymorphisms (SNPs) associated with MUD. Principle component analysis (PCA) was performed to investigate the effects of population stratification on the outcome of this analysis. Subsequently, associated SNPs from the MUD and CUD cohorts were investigated using in silico analyses to determine host genes for associated SNPs. These genes were compared to identify those exclusive to the MUD cohort, and were subsequently enriched to identify associated biological pathways and miRNA. The regression analysis identified 510 SNPs approaching significant association (p<1x10-4) with MUD. The genes identified in the MUD and CUD cohorts were compared, which led to the identification of 57 genes exclusively associated with the MUD cohort. These genes were found to be associated with several pathways involved in the aetiology of MUD such as autophagy and apoptosis. The genes were also regulated by miRNA previously associated with MUD. In conclusion, this study was able to identify several miRNA and genes trending towards significance. These findings are consistent with the current literature on MUD and contribute to knowledge on the molecular underpinnings of MUD by highlighting differences between MUD and other stimulant use disorders. The findings identify an epigenetic component to MUD aetiology via miRNA and speak to underlying regulatory networks involved in MUD aetiology. This is the first study investigating the molecular underpinnings of MUD in a South African cohort, indicating the potential for use of local populations to identify novel variants associated with miRNA-mediated regulation in MUD aetiology.