Investigating the role of miRNA-mediated regulation in antipsychotic treatment response in a South African first-episode schizophrenia cohort

Hamilton, Megan April (2020-03)

Thesis (MScAgric)--Stellenbosch University, 2020.

Thesis

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 neuropsychiatric disorders, the heritability of such disorders and associated traits such as treatment response are not completely understood. Antipsychotic treatment response (ATR) of schizophrenia (SZ) is effective in only around half of all diagnosed patients. As with the disorder itself, ATR is known to be a complex trait with variable outcomes for patients and for which no clinical biomarkers exist 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 to elucidate this ‘missing heritability’ seen in ATR outcomes, in combination with pharmacogenetics approaches which aim to quantify on an individual level the interaction between genetics and maximal treatment efficacy, as well as in avoidance of potential adverse drug reactions (ADRs). The data outputs from GWAS have also highlighted noncoding regions of the genome, in which many top resultant hits have been shown to occur, in spite of this the interpretation of many genomic results have been limited to the nearest gene. While genetic variants linked to aspects of treatment like ATR and ADRs have been found, the interpretation of such results are important in discerning functional consequence surrounding identification of single nucleotide polymorphisms (SNPs) in association with either disorder or trait surrounding the disorder, i.e. ATR. These findings in combination with the knowledge of noncoding regions prominent role in hosting many SNPs, draws attention to the potential role of regulatory mechanisms interacting within ATR systems or pathways that have otherwise 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 miRNA-targeted genes in a bioinformatic systems genetics approach to reveal underlying regulatory consequences interacting in SZ ATR. The most significant finding identified a novel association of the variant, rs895808, with an improved treatment response for the negative symptom domain of the Positive and Negative Syndrome Scale (PANSS). The SNP was found to have consequential impact in 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 analysis identified implicated pathways from miRNA-targeted genes and SNPs, with regulation of apoptosis and phosphodiesterase pathways presenting. Both pathways have largely been implicated in SZ pathophysiology, however this is the first identification with regard to miRNA-involvement to our knowledge and suggests an alternate avenue for investigation into the ATR of SZ.

AFRIKAANSE OPSOMMING: Alhoewel aansienlik baie vordering in geonomiese navorsing, soos die van Genoomwye Assosiasiestudies (GWAS), tot groot hoeveelhede geonomiese data aangaande die genetiese basis van baie neuropsigiatriese toestande gelei het - word die oorerflikheid van sulke toestande en geassosieerde kenmerke soos behandelingsrespons nog nie volledig verstaan nie. Die antipsigotiese behandeling van skisofremie (SZ) is slegs effektief in min of meer die halfte van gediagnoseerde pasiente. Nes die toestand self is die antipsigotiese behandelingsrespons (ATR) bekend daarvoor om ‘n ingewikkelde eienskap te wees met veelvuldige moontlike uitkomste vir pasiente. Daar bestaan ook geen klieniese biomerkers om moontlike behandelingseffektiwiteit meer aan te dui nie, en behandeling gaan dikwels gepaard met steekproef proses van probeer en aanpas tot en met sukses behaal word. Die grootskaalse natuur van studies soos GWAS die potensiaal om hierdie ‘onbekende oorerflikheid’ wat in ATR gesien word te verklaar. In kombinasie daarmee help farmakogenetiese benaderings wat die interaksie tussen genetika en maksimum behandelingseffektiwitiet, asook vermyding van potensiële ongunstige medisyne reaksies (ADRs) om op ‘n indivduële vlak te teiken. Die dataopbrengste van GWAS het ook nie nie-koderende streke van die genoom uitgewys waarin baie van die mees gereëlde vangskote voorgekom het. Ten spyte van hiervan is die interpretasie van baie geonomiese uitkomstes beperk tot die naaste enkele geen. Terwyl genetiese variante gekoppel aan behandelingsaspekte soos ATR en ADRs al gevind is, is die interptretasie van hierdie data baie belangrik. Dit kan gebruik word om die funksionële nagevolge rondom die identifikasie van enkel nukleotied polimorfismes (SNPs) te onderskei, in genootskap met die toestand of ‘n kenmerk van die toestand - d.w.s ATR. Hierdie bevindinge, tesame met die kennis van die prominente rol wat niekoderende streke speel in die huisvesting van SNPs vestig aandag op die potensiële rol van beherende meganismes wat op mekaar inwerk binne ATR sisteme of padweë wat andersins ter syde gesit sou word. Hierdie studie het die rol van miRNA-bemiddelde regulasie in ATR ondersoek, met paralelle benaderinge ontwerp om die potensiaal van miRNA geimpliseerd in SNPs en miRNA-geteikende gene in bioinformatiese sisteemsgenetieka te ondersoek om onderliggende beheersnagevolge wat met SZ ATR verkeer. Die mees betekenisvolle bevinding was ‘n nuwe assosiaise van die rs895808 variant, wat ‘n verbeterde behandelingsrespons vir negatiewe simptome op die Positiewe- en Negatiewe Sindroomskaal (PANSS). Dié SNP was gevind om gevolglike impak te om die gekonserfeerde streke van volgende miRNAs te versteur: miRNA-548ac, miRNA-548d-3p, miRNA548h-3p en miRNA-548z. Dit is ook gekoppel aan miRNA-4536 met onbekende beherende impak. FUMA analise het padweë van geimpliseerde miRNA-geteikende gene geïdentifiseer, asook SNPs wat apoptose en fosodïesterase padweë reguleer. Beide padweë is grotendeels geïmpliseerd in SZ patofisiologie, alhoewel dit die eerste identifikasie met betrekking tot miRNA is en ‘n alternatiewe roete vir ondersoek van ATR van SZ is.

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