Genomic characterization of human traits associated with polyglutamine disease genes and modifiers

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dc.contributor.authorNamuli, Kevin Lucy
dc.contributor.examiningcommitteeKowalec, Kaarina (Pharmacy)
dc.contributor.examiningcommitteeMiller, Donald (Pharmacology and Therapeutics)
dc.contributor.supervisorWright, Galen
dc.contributor.supervisorDrögemoller, Britt
dc.date.accessioned2024-08-29T19:56:58Z
dc.date.available2024-08-29T19:56:58Z
dc.date.issued2024-08-26
dc.date.submitted2024-08-27T17:25:42Zen_US
dc.degree.disciplinePharmacology and Therapeutics
dc.degree.levelMaster of Science (M.Sc.)
dc.description.abstractBackground: Polyglutamine (polyQ) diseases, such as Huntington disease (HD) and certain spinocerebellar ataxia, are a group of severe neurodegenerative disorders caused by duplication of the glutamine codon. These conditions currently lack effective treatments, and most therapeutics in development are focused on pathogenic gene knockdown, which may have unintended consequences. Objective: We aimed to profile polyQ disease genes to guide therapeutic interventions by identifying potential off-target effects. Methods and Results: We performed an unbiased phenome-wide study to identify traits linked to polyQ genes by analyzing Open Targets Genetics Database data. We curated 3,095 traits associated with polyQ genes. Applying a locus-to-gene filtering threshold of 0.5 that quantifies the strength of evidence (0 to 1, higher scores signifying increased strength), we retained 215 gene associations, encompassing both disease and non-pathogenic traits, including neurological outcomes and suggesting adverse outcomes associated with gene knockdown. We further assessed the theoretical druggability of these genes and revealed that polyQ genes may not be favorable therapeutic targets suggesting the need to explore alternative rational targets such as modifiers. We prioritized HD for further analysis as it is the most well-studied polyQ disorder, with large cohorts of affected individuals recruited for human genetic studies, therefore, providing a framework to understand other polyQ disorders. Further analysis involved fine-mapping, a technique used to pinpoint variants, of the HD onset GWAS to identify candidate variants and genes modifying disease onset. We applied a functionally informed fine-mapping strategy to refine credible sets of causal variants at significant risk regions (p < 5x10-6). We used a posterior inclusion probability filtering threshold of 0.5 to identify potential causal variants. We prioritized eight candidate variants, including five previously reported signals, and three new ones. A subset of these signals harboured missense variants associated with DNA repair genes (i.e., MLH1, MSH3, FAN1, LIG1). Notably, two new variants, rs149892574 and rs2798373, were identified as potentially modifying HD onset through changing enhancer and promoter sequences. Conclusion: Altogether, our analysis highlights the need to consider alternative therapeutic options for polyQ disorders and further prioritizes HD onset modifiers that require functional validation and can be extended to other polyQ disorders.
dc.description.noteOctober 2024
dc.description.sponsorshipNatural Sciences and Engineering Research Council of Canada (Canada Research Chair: Neurogenomics, Award Number: CRC-2019-145), Health Sciences Centre Foundation General Operating Grant (Fine-mapping of neurodegenerative disorder genomic risk loci for the prioritization of novel drug targets), Research Manitoba (Funder Identifier: http://dx.doi.org/10.13039/100008794)
dc.identifier.urihttp://hdl.handle.net/1993/38457
dc.language.isoeng
dc.rightsopen accessen_US
dc.subjectPolyglutamine disorders
dc.subjectGenome-wide association studies
dc.subjectFine-mapping
dc.subjectNeurodegenerative disorders
dc.subjectHuntington disease
dc.titleGenomic characterization of human traits associated with polyglutamine disease genes and modifiers
dc.typemaster thesisen_US
local.subject.manitobano
oaire.awardNumberRGPIN-2022-04509
oaire.awardTitleGenomics of DNA repair in the brain
project.funder.identifierhttp://dx.doi.org/10.13039/501100000038
project.funder.nameNatural Sciences and Engineering Research Council of Canada Discovery Grant
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