Background: 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.