Unbiased human genomic characterization of polyglutamine disorder genes to guide biological understanding and therapeutic strategies.

Polyglutamine (polyQ) disorders, such as Huntington disease (HD) and several spinocerebellar ataxias, are severe neurological disorders caused by glutamine codon repeat expansions. These conditions lack effective treatments, with therapeutic research focused on pathogenic gene knockdown. This investigation aimed to profile these genes using diverse human genomic data to inform therapeutic strategies by identifying new biology and assessing the potential on-target effects of knocking down these genes. 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 with repeat expansion (HD) modifier genes. Our analyses identified 215 human phenotype/polyQ disorder gene associations from 3,095 studies, indicating potential adverse effects from gene knockdown. Shared trait associations among genes suggested overlapping biological processes despite distinct functions. Drug target profile analysis revealed increased safety concerns due to genomic features (i.e., constraint, molecular interactions, and tissue specificity) for polyQ disorder genes, particularly ATN1, ATXN1, ATXN7, and HTT. PolyQ disorder genes also showed significantly more safety-related risks than HD genetic modifier genes (p = 7.03 × 10-3). In conclusion, our analyses emphasize the pleiotropic nature of polyQ disorder genes, highlighting their potential risks as drug targets. These findings reinforce the importance of exploring alternative therapeutic strategies, such as targeting genetic modifier genes, as well as allele-selective approaches, to mitigate these challenges.