The role of DNA methylation in the aetiology of anxiety proneness in a cohort of South African adolescents: an exploratory study

Zass, Lyndon (2017-03)

Thesis (MSc)--Stellenbosch University, 2017.

Thesis

ENGLISH ABSTRACT: Anxiety disorders are a range of complex disorders characterised by abnormal anxiety in the absence of anxiety-provoking stimuli. The aetiology of anxiety disorders is attributed to interaction between genetic and environmental factors. It is crucial to identify and characterise risk factors that result in the development of anxiety disorders in adulthood. Anxiety proneness (AP) is one such risk factor and represents an endophenotype for anxiety disorders. Several studies have previously associated hypothalamic- pituitary- adrenal (HPA) axis related genes with anxiety disorder development, however these studies generally do not account for environmental contributors. Epigenetics provides a mechanism to study environment and gene interaction. DNA methylation is a well-studied epigenetic modification with the ability to influence gene expression. The present study aimed to investigate the role that genome-wide alterations in DNA methylation play in the development of AP by investigating South African adolescents who have experienced differing levels of childhood trauma (n = 63). The Illumina HumanMethylation450K BeadChip array was used to conduct genome-wide DNA methylation analysis on 46 individuals. EpiTYPER MassARRAY technology was used to verify selected differentially methylated genes from the initial analysis, as well as to analyse additional HPAaxis related genes. Several genes were found to be differentially methylated prior to correction for multiple testing, and the majority of these had designated brain functions. Additionally, a significant trend in methylation was observed in the promoter region of the serotonin transporter gene (SLC6A4). In conclusion, the current study indicates a role for the methylation of SLC6A4 in the development of AP in South African adolescents, however these results need to be replicated in a larger study sample.

AFRIKAANSE OPSOMMING: Angsversteurings beskryf 'n verskeidenheid van komplekse siektes wat gekenmerk word deur abnormale angs in die afwesigheid van angs uitdagende stimuli. Die etiologie van angsversteurings word toegeskryf aan die interaksie tussen genetiese- en omgewings faktore. Daarom is dit noodsaaklik om risiko faktore wat lei tot die ontwikkeling van volwasse angsversteurings te identifiseer. Angs geneigheid verteenwoordig een van hierdie sogenoemde risiko faktore. Angs geneigheid verteenvoordig 'n angsversteurings endofenotipe wat in die huidige studie ondersoek word. Verskeie studies het voorheen hipotalamus-pituïtêre-adrenale siklus (HPA) verwante gene met die ontwikkeling van angsversteurings assosieer. Oor die algemeen, neem hierdie studies egter nie die bydrae van omgewings faktore in ag tydens analise nie. Epigenetika bied 'n metode om die interaksie tussen genetiese en omgewings faktore te bestudeer. DNS-metilering is 'n goed-bestudeerde epigenetiese modifikasie met die vermoë om geenuitdrukking te beïnvloed. Die huidige studie het ten doel om die rol wat genoom-wye veranderinge in DNS-metilering in die ontwikkeling van AP speel te ondersoek. Hierdie doel was bereik deur Suid-Afrikaanse tieners wat verskeie vlakke van trauma ervaar het tydens hul kinderjare, te ondersoek (N = 63). Die Illumina HumanMethylation450K BeadChip tegnologie is gebruik om genoom-wye DNS-metilering analise uit te voer op 46 individuele. Daarbenewens is die EpiTYPER MassARRAY tegnologie gebruik om selektiewe differensieël gemetileerde gene vanaf die aanvanklike ontleding te verifieer asook bykomende HPAverwante gene te analiseer. Verskeie differensieel gemetileerde gene was identifiseer voor statistiese korreksie vir veelvuldige toetsing. Die meerderheid hiervan besit toegeskrewe breinfunksies. Daarbenewens was 'n beduidende neiging in metilering ook waargeneem in die promotor streek van die serotonien karweier geen (SLC6A4). Ten slotte, dui die huidige studie op 'n moontlike rol vir die metilering van SLC6A4 in die ontwikkeling van AP in Suid-Afrikaanse tieners. Hierdie resultate moet egter herhaal word in 'n groter studie monster.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/101358
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