Investigating the role of miRNA-mediated regulation in antipsychotic treatment response in a South African first-episode schizophrenia cohort
Year: 2020
Type: dissertation
Study design: Observational Study
Abstract: ENGLISH ABSTRACT: Although considerable advances in genomics research, with the likes of Genome-Wide Association Studies (GWAS), have uncovered vast quantities of genomic data regarding the genetic basis of many \nneuropsychiatric disorders, the heritability of such disorders and associated traits such as treatment \nresponse are not completely understood. Antipsychotic treatment response (ATR) of schizophrenia \n(SZ) is effective in only around half of all diagnosed patients. As with the disorder itself, ATR is \nknown to be a complex trait with variable outcomes for patients and for which no clinical biomarkers \nexist to point towards possible indicators of treatment efficiency, often accompanied by the trial-anderror process of treatment adjustment. The large-scale nature of studies like GWAS, have the potential \nto elucidate this ‘missing heritability’ seen in ATR outcomes, in combination with pharmacogenetics \napproaches which aim to quantify on an individual level the interaction between genetics and \nmaximal treatment efficacy, as well as in avoidance of potential adverse drug reactions (ADRs). The \ndata outputs from GWAS have also highlighted noncoding regions of the genome, in which many top \nresultant hits have been shown to occur, in spite of this the interpretation of many genomic results \nhave been limited to the nearest gene. While genetic variants linked to aspects of treatment like ATR \nand ADRs have been found, the interpretation of such results are important in discerning functional \nconsequence surrounding identification of single nucleotide polymorphisms (SNPs) in association \nwith either disorder or trait surrounding the disorder, i.e. ATR. These findings in combination with \nthe knowledge of noncoding regions prominent role in hosting many SNPs, draws attention to the \npotential role of regulatory mechanisms interacting within ATR systems or pathways that have \notherwise been disregarded. This study investigated the role of miRNA-mediated regulation in ATR, with parallel approaches designed to investigate the potential of miRNA implicated SNPs and \nmiRNA-targeted genes in a bioinformatic systems genetics approach to reveal underlying regulatory \nconsequences interacting in SZ ATR. The most significant finding identified a novel association of \nthe variant, rs895808, with an improved treatment response for the negative symptom domain of the \nPositive and Negative Syndrome Scale (PANSS). The SNP was found to have consequential impact \nin disrupting the following miRNAs conserved sites; miRNA-548ac, miRNA-548d-3p, miRNA548h-3p and miRNA-548z, and is linked to miRNA-4536 with unknown regulatory impact. FUMA \nanalysis identified implicated pathways from miRNA-targeted genes and SNPs, with regulation of \napoptosis and phosphodiesterase pathways presenting. Both pathways have largely been implicated \nin SZ pathophysiology, however this is the first identification with regard to miRNA-involvement to \nour knowledge and suggests an alternate avenue for investigation into the ATR of SZ.
Author: Megan April Hamilton
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3040977175