An investigation into the molecular genetics of Major Depressive Disorder

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dc.check.chapterOfThesisWhen submitting the thesis I had requested that the thesis be fully restricted as the method developed in this thesis is proprietry and being evaluated for patent filingen
dc.check.date9999-12-31
dc.contributor.advisorMcCarthy, Tommie V.
dc.contributor.authorBogue, Roisin
dc.contributor.funderSchool of Biochemistry and Cell Biologyen
dc.date.accessioned2025-05-21T15:01:57Z
dc.date.available2025-05-21T15:01:57Z
dc.date.issued2025
dc.date.submitted2025
dc.description.abstractMajor Depressive Disorder (MDD) is a debilitating psychiatric condition with a complex aetiology involving both genetic and environmental factors. Despite its high prevalence and significant impact on global health, the precise biological underpinnings of MDD remain poorly understood, hindering the development of effective diagnostic and therapeutic strategies. This thesis addresses this critical gap by focusing on two main objectives: the identification of causative genes through linkage analysis and rare variant analysis in a human pedigree and the identification and validation of biomarkers for MDD using a rat maternal separation model. The first part of the thesis focused on a unique pedigree dataset characterised by a high incidence of mood disorders, particularly MDD, with unusually severe symptoms in a high number of affected individuals. The dataset, collected over a >30-year period, includes data from multiple sources, such as SNP arrays, exon arrays, whole exome sequencing (WES), and whole genome sequencing (WGS). Due to the length of the collection period, the data reflects a range of technological advancements in sequencing approaches. For linkage analysis these diverse datasets were combined, and the samples were stratified based on diagnostic severity criteria. Linkage analysis identified two key regions, a locus on chromosome 12q24, associated with a severe phenotype, and on chromosome 4q15, associated with a moderate phenotype, both of which co-segregate with a large number of affected individuals within the pedigree. Additionally, analysis of rare variants using WGS data, which was available for a subset of the pedigree, identified a rare variant in the STIM2 gene with an allele frequency of 0.00001002 and present in 15 affected members of the pedigree. This variation replaces an arginine (R) with a tryptophan (W) at amino acid position 25 in the STIM2 protein. Prediction software used to assess this R25W variant suggests that it is likely to have an impact on the function of the STIM2 protein. Additionally, Eukaryotic Linear Motif (ELM) analysis revealed that the mutation potentially disrupts a putative endoplasmic reticulum (ER) retention/retrieval motif. Conservation analysis of the associated sequence indicated the regions surrounding the SNP is conserved in higher-order mammals, further supporting the potential significance of this variant. The second part of this thesis employed the well-established rat maternal separation model, for inducing depressive-like behaviours to investigate the feasibility of a novel method for biomarker discovery in complex disease. The method utilises plasma from different disease states to identify compositional differences which can be used to stratify samples. This method can theoretically be applied to blood derived samples from a number of conditions. Using this method maternally separated rats and non-separated controls clustered into three distinct groups which correlated highly with forced swim test (FST) immobility counts, an established measure of depressive-like behaviour, allowing the creation of a biomarker panel. This feasibility study suggests that the method described could have broad application across many complex diseases where biomarkers are currently lacking. Together, these two approaches, combining genetic analysis of a unique pedigree with a high incidence of MDD and biomarker discovery using a rat maternal separation model, provides a comprehensive exploration of the genetic and biological factors associated with MDD. The identification of two key genomic regions, the discovery of a rare variant in the STIM2 gene, and the development of a biomarker panel offer insights into the potential mechanisms of depression. While these findings deepen our understanding of MDD, they also underscore the complexity of the disorder, and prompt further research to validate these results and better understand their potential implications for diagnosis, disease progression and treatment.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationBogue, R. 2025. An investigation into the molecular genetics of Major Depressive Disorder. PhD Thesis, University College Cork.
dc.identifier.endpage239
dc.identifier.urihttps://hdl.handle.net/10468/17555
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2025, Roisin Bogue.
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectMajor Depressive Disorderen
dc.subjectBiomarkersen
dc.titleAn investigation into the molecular genetics of Major Depressive Disorder
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD - Doctor of Philosophyen
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