Background: Polyglutamine (polyQ) disorders, such as Huntington disease (HD) and several spinocerebellar ataxias, are severe neurological disorders caused by repeat expansions of the glutamine codon. These conditions lack effective treatments, with therapeutic research focused on pathogenic gene knockdown. We aimed to profile these genes using diverse human genomic data to guide therapeutic strategies by identifying new biology and assessing off-target effects of knocking these genes down. Methods: We conducted an unbiased phenome-wide study to identify human traits and diseases linked to polyQ disorder genes (Open Targets L2G>0.5). Network analyses explored shared trait associations and overlapping biological processes among these genes. Lastly, we assessed the theoretical druggability of polyQ disorder genes using recently identified features predictive of clinical trial success and compared them to repeat expansion (HD) modifier genes. Results: We identified 215 human phenotype/polyQ disorder gene associations from 3,095 studies, indicating potential adverse effects from gene knockdown. Shared trait associations among polyQ disorder genes suggested overlapping biological processes despite distinct functions. Drug target profile analysis revealed an unfavorable risk profile for polyQ disorder genes, particularly ATN1, ATXN1, ATXN7, and HTT, due to genomic features such as constraint, molecular interactions, and tissue specificity. PolyQ disorder genes also showed significantly more safety-related risks than HD modifier genes (P=7.03x10-3). Conclusion: Our analyses emphasize the pleiotropic nature of polyQ disorder genes, highlighting their potential risks as drug targets due to safety concerns. These findings reinforce the importance of exploring alternate therapeutic strategies, such as targeting genetic modifier genes, to mitigate these challenges.

The authors have declared no competing interest.

We thank the Natural Sciences and Engineering Research Council of Canada through the Canada Research Chairs Initiative and Discovery Grant Program, as well as the Health Sciences Centre Foundation Winnipeg, for the financial support provided to GEBW. BID was also supported through the Canadian Institutes of Health Research Canada Research Chairs Initiative. The Research Manitoba Graduate Studentship and Rady Faculty of Health Sciences Student Top-Up supported NKL.

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The Bannatyne Research Ethics Board of the University of Manitoba gave ethical approval for this work.

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The data used in the analyses described in this study are publicly accessible to researchers through the consortia that generated them. Analysis scripts for data accession, analysis and visualization are accessible at https://github.com/Wright-Lab-Neurogenomics-Research/polyQ_genes_characterization_analyses