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An integrative data-analysis of miRNA-related contributions to the pathophysiology of neuropsychiatric disorders
Thesis (MScAgric)--Stellenbosch University, 2022.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2022
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| _version_ | 1867613790367907840 |
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| access_status_str | Open Access |
| author | Prinsloo, Hendrik Johannes |
| author2 | McGregor, Nathaniel W. |
| author_browse | McGregor, Nathaniel W. Prinsloo, Hendrik Johannes |
| author_facet | McGregor, Nathaniel W. Prinsloo, Hendrik Johannes |
| author_sort | Prinsloo, Hendrik Johannes |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (MScAgric)--Stellenbosch University, 2022. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/126094 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:41:44.687Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2022 |
| publishDateRange | 2022 |
| publishDateSort | 2022 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/126094 An integrative data-analysis of miRNA-related contributions to the pathophysiology of neuropsychiatric disorders Prinsloo, Hendrik Johannes McGregor, Nathaniel W. Stellenbosch University. Faculty of AgriSciences. Dept. of Genetics. Antipsychotic treatment response MicroRNA -- Mechanism of action Neuropsychiatry Schizophrenia -- Treatment Synaptic plasticity Neuropsychiatric disorders -- Pathophysiology First episode schizophrenia -- Patients UCTD Thesis (MScAgric)--Stellenbosch University, 2022. 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. AFRIKAANSE OPSOMMING: Die nadelige effek van neuropsigiatriese versteurings (NVs) belemmer groei op die samelewing sowel as op ‘n persoonlike vlak. Hierdie is veral van toepassing op ontwikkelende lande waar antipsigotiese behandeling onvoldoende is. Daarbenewens, is antipsigotiese behandelings oneffektief en die eensydigheid van populasie groepe in mediese navorsing is moontlik bydraend tot verswakte antipsigotiese behandelings reaksie (ABR) van onder bestudeerde populasies. Ten spyte van die groeiende lys van potensiële biomerkers vir komplekse siektes het die veld van psigiatrie min kliniese bevordering getoon in beide diagnose en ABR. Mikro-RNA (miRNA) het onlangs die voortrou geneem in NV etiologie as gevolg van die hoë vlakke van miRNA wat in die sentrale senuwee stelsel van soogdiere uitgedruk word. Dit word geglo dat miRNA moontlik ‘n invloed op ABR kan hê deur die regulering van sinaptiese plastisiteit. Hierdie gevolgtrekking is gemaak as gevolg van die bestaande verhouding tussen die omgewing, miRNA gene regulasie en neuroadaptasie. In hierdie verband is sinaptiese plastisiteit gene voorheen sterk geïmpliseer in NV etiologie en party miRNA het selfs betekenisvolle assosiasie in genome wye assosiasie studies gevind in versteurings soos skisofrenie (SCZ). Ten spyte van die is daar steeds baie onbekendheid rondom die ingewikkelde netwerk tussen miRNA en ABR. Variasie in miRNA-teiken interaksie kan moontlik insig lewer ten opsigte van differensiële ABR en selfs nadelige behandelings reaksies. Die huidige studie het ten doel om miRNA bindings variasie in sinaptiese plastisiteit gene te beskryf in ‘n poging om lig te werp op differensiële behandelings uitkomstes. Daarby was die unieke genetiese vermenging van die Suid Afrikaanse steekproef gebruik om die invloed van herkoms te ondersoek in die konteks van ABR. Die Suid Afrikaanse steekproef bestaan uit 103 behandelings naïef eerste episode skisofrenie (EES) pasiënte wat almal met dieselfde langwerkende inspuitbare antipsigotiese medikasie, bekend as “flupenthixol decanoate”, behandel is. Psigotiese simptome was oor ‘n tydperk van 12 maande aangeteken deur gebruik te maak van die Positiewe en Negatiewe Sindroom Skaal (PANSS). Sinaptiese plastisiteit kandidaat gene is gebruik om ‘n bioinformatiese pyplyn te begin met die doel om genetiese variasie in miRNA bindings setels te identifiseer. Die variante is gevolglik getoets vir assosiasie met ABR deur lineêre regressie en gemengde effek modellering. Assosiasie is gevind in ses variante in onderskeie simptoom kategorieë. Van belang was die assosiasie tussen rs635903 en slegs negatiewe simptome, sowel as die sterk assosiasie tussen rs3735666 met beide totale en negatiewe simptome. Beide hierdie variante lei tot differensiële miRNA binding en gevolglik tot differensiële regulering sterkte van hulle teiken gene. Daarbenewens is betekenisvolle variante gebruik om pasiënte volgens reaksie te groepeer en ‘n duidelike assosiasie is gesien tussen Europese herkoms en die meer responsiewe groep. Verder was die Afrika San populasie groep meer geneig om in die minder responsiewe groep te val. Hierdie bevinding versterk die aanname dat die Eurosentriese fokus van mediese navorsing lei tot verswakte reaksie in onder verteenwoordigde populasies. Die huidige studie lig dus toe die rol van miRNA bindings variasie in ABR en lig uit die belang daarvan om vermengde herkoms individue in mediese navorsing in te sluit met die doel om te verbeter op behandelings uitkoms. Die veld van medikasie ontwikkeling kan voordeel trek deur hierdie aspekte in ag te neem om meer effektiewe maniere te vind om pasiënte te diagnoseer en te behandel in versteurings soos SCZ. Masters 2022-11-23T10:17:50Z 2023-01-16T12:49:47Z 2022-11-23T10:17:50Z 2023-01-16T12:49:47Z 2022-12 Thesis http://hdl.handle.net/10019.1/126094 en_ZA Stellenbosch University xii, 74 pages : illustrations (some color) application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Antipsychotic treatment response MicroRNA -- Mechanism of action Neuropsychiatry Schizophrenia -- Treatment Synaptic plasticity Neuropsychiatric disorders -- Pathophysiology First episode schizophrenia -- Patients UCTD Prinsloo, Hendrik Johannes An integrative data-analysis of miRNA-related contributions to the pathophysiology of neuropsychiatric disorders |
| title | An integrative data-analysis of miRNA-related contributions to the pathophysiology of neuropsychiatric disorders |
| title_full | An integrative data-analysis of miRNA-related contributions to the pathophysiology of neuropsychiatric disorders |
| title_fullStr | An integrative data-analysis of miRNA-related contributions to the pathophysiology of neuropsychiatric disorders |
| title_full_unstemmed | An integrative data-analysis of miRNA-related contributions to the pathophysiology of neuropsychiatric disorders |
| title_short | An integrative data-analysis of miRNA-related contributions to the pathophysiology of neuropsychiatric disorders |
| title_sort | integrative data analysis of mirna related contributions to the pathophysiology of neuropsychiatric disorders |
| topic | Antipsychotic treatment response MicroRNA -- Mechanism of action Neuropsychiatry Schizophrenia -- Treatment Synaptic plasticity Neuropsychiatric disorders -- Pathophysiology First episode schizophrenia -- Patients UCTD |
| url | http://hdl.handle.net/10019.1/126094 |
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