Evaluation of novel genetic and pharmacogenetic targets in depression

Author: Sha Liu

Liu, Sha, 2017 Evaluation of novel genetic and pharmacogenetic targets in depression, Flinders University, School of Medicine

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Major Depressive Disorder (MDD) is a prevalent multifactorial disorder of unknown aetiology with enormous economic, medical and social impact globally. MDD is also a leading cause of suicide and the third highest fatal disease burden in Australia men. It is treated with antidepressants, which are safe and tolerable drugs. Even though their efficacy in MDD treatment is well proven by double-blind, randomised controlled trials, some patients fail to respond to some antidepressant drugs, which leads to several trials of different medications to obtain clinical improvement. One factor for such variable antidepressant response is genetic variation. Previous work in our lab has aimed at understanding the genetic basis for MDD susceptibility focusing on functional single nucleotide polymorphisms. Our lab has identified several human genetic variations that may be associated with either MDD susceptibility or remission to antidepressant treatment. A variation significantly associated with antidepressant treatment remission has been located in a potential brain DNA immunoprecipitation sequencing site suggesting that it might be involved in epigenetic regulation of neuronal gene expression. Therefore, our research aims were to characterise genes that our group has identified as potentially associated with MDD diagnosis or antidepressant response. In a rodent model of depression, we have studied expression levels of potential risk genes in the rat hippocampus in response to chronic stress. To achieve our goals, we induced depressive-like behaviour using a chronic restraint stress (CRS) paradigm, where the rats were held in a flat-bottom clear acrylic restraint for 6 hours per day for 14 consecutive days. Behavioural tests were performed at baseline and after 14 days of restraint to confirm the presence of depressive-like behaviour. After completion of behavioural testing, rats were euthanized between 10AM-noon to avoid the confounding effects of circadian rhythms. Quantitative real-time polymerase chain reaction (qPCR) analysis and Western blot analysis were performed in order to study expression levels of potential risk genes in rat hippocampus. In these studies, we identified that mRNA levels for the gene Phf21b, Argap8, Trpm2 and four other genes were significantly changed in response to chronic restraint stress or social isolation. Additionally, we also have addressed that the relative protein level of PHF21B and ARHGAP8 changed significantly between CRS and control groups. Brain quantitative trait loci analysis revealed that the genes that changed significantly in response to stress or social isolation also have variants that significantly change gene expression in post-mortem brain regions. These findings revealed the involvement of our risk genes in the mechanisms of CRS response, and discovered potential therapeutic targets for the development of novel antidepressants.

Keywords: Major Depressive Disorder, Mexican-American individuals, European-ancestry individuals, chronic restraint stress, Phf21b, Arhgap8, Trpm2, Cntanp1, Unc13d, Cwc22, Syncrip

Subject: Medicine thesis

Thesis type: Doctor of Philosophy
Completed: 2017
School: School of Medicine
Supervisor: Professor Ma-Li Wong