Doctoral Degrees (Psychiatry)

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Browsing Doctoral Degrees (Psychiatry) by browse.metadata.advisor "Hemmings, Sian"

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    The identification of novel susceptibility genes involved in anxiety disorders
    (Stellenbosch : Stellenbosch University, 2014-12) McGregor, Nathaniel Wade; Lochner, Christine; Hemmings, Sian; Kinnear, Craig; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Psychiatry.
    ENGLISH ABSTRACT: The etiology of anxiety disorders remains incompletely understood. Clear evidence for a genetic component has been proposed; however, there is also an increasing focus on environmental factors and the interaction between these and the genetic components that may mediate (anxiety) disorder pathogenesis. No single gene or genetic component has been explicitly identified as being involved in the development of anxiety disorders. This is most likely due to a number of reasons, which include, for example, the heterogeneity of anxiety disorders, the contribution of environmental factors and methodological limitations (e.g. small sample size) of research studies. Until now, genetic association studies usually focused on one particular psychiatric disorder at a time. However, with the difficulty in identifying susceptibility genes and/or loci in heterogeneous disorders like obsessive-compulsive disorder and other conditions in the anxiety spectrum, it is perhaps timely to consider multivariate genetics and epidemiological studies in a number of disorders sharing a core characteristic – such as anxiety. In addition to genetic underpinnings, a number of environmental variables have also been identified as risk factors for pathological anxiety, including adverse life events like childhood physical and sexual abuse. The hypothesis for this project is that a pre-existing genetic vulnerability (or genetic risk) interacts with the impact of adverse life events to result in the development of one or more anxiety disorder(s). Considering phenotypic overlap amongst the anxiety disorders, it is likely that diverse networks of genes and/ or interacting pathways are responsible for the phenotypic manifestations observed. Sprague Dawley rats exhibiting behaviours indicative of anxiety in the context of environmental stressors (maternal separation and restraint stress) were used as model for the identification of novel susceptibility genes for anxiety disorders in humans. The striatum has previously been implicated as a candidate in the brain architecture of anxiety pathogenicity, and is also a site exhibiting a high degree of synaptic plasticity. The synaptic plasticity pathway was investigated using the dorsal striatum of the rat brain and several genes were identified to be aberrantly expressed in “anxious” rats relative to controls (Mmp9, Bdnf, Ntf4, Egr2, Egr4, Grm2 and Arc). In humans, it was found that the severity of early adversity was significantly and positively associated with the presence of an anxiety disorder in adulthood. When the human homologues of the susceptibility candidate genes that were identified using the animal model were screened in a human cohort of patients with obsessive-compulsive disorder (OCD), panic disorder (PD) or social anxiety disorder (SAD) (relative to controls), five single nucleotide polymorphisms (SNPs) were found to be significantly associated with these conditions. Four of these SNPs were also found to significantly interact with the severity of childhood trauma. Haplotype analysis of variants within the identified susceptibility candidates revealed novel haplotype associations, four of which are located in the MMP9 gene. Notably, this the first study to link these particular mutations in the MMP9 gene with anxiety disorders and this finding is consistent with previous work suggesting that MMP9 is involved in conditions like cardiovascular disease and cancer which have been associated with increased prevalence of anxiety disorders. In conclusion, this project yielded important findings pertaining to the etiology of anxiety disorders. The use of a combined anxiety disorders cohort (OCD, PD and SAD) may suggest that the associations found here may hold true for anxiety disorders in general and not only for a particular clinically delineated condition. Childhood trauma was confirmed as an increased susceptibility risk for anxiety disorders. Also, this research contributed several novel susceptibility genes (MMP9, EGR2, EGR4, NTF4, and ARC), five significant SNP associations, four significant SNP-environment interactions and five haplotype associations (within MMP9 and BDNF) as candidates for anxiety pathogenicity. The identified polymorphisms and haplotypes were demonstrated to be associated with susceptibility to anxiety disorders in a gene-environment correlation and gene-environment interaction.