Genomic characterization of Huntington’s disease genetic modifiers informs drug target tractability

Huntington's disease is caused by a CAG repeat in the <i>HTT</i> gene. Repeat length correlates inversely with the age of onset but only explains part of the observed clinical variability. Genome-wide association studies highlight DNA repair genes in modifying disease onset, but further research is required to identify causal genes and evaluate their tractability as drug targets. To address these gaps and learn important preclinical information, we analysed genome-wide association study data from a large Huntington's disease age-of-onset study (<i>n</i> = 9064), prioritizing robust candidate Huntington's disease modifier genes using bioinformatic approaches and analysing related information for these genes from large-scale human genetic repositories. We supplemented this information with other Huntington's disease-related screens, including exome studies of Huntington's disease onset and high-throughput assessments of mHTT toxicity. To confirm whether Huntington's disease modifiers are shared across repeat expansion disorders, we also analysed age-of-onset genome-wide association study data from X-linked dystonia-parkinsonism caused by a (CCCTCT)_n expansion. We also studied modifier-related associations with rare diseases to inform potential off-target therapeutic effects and conducted comprehensive phenome-wide studies to identify other traits linked to these genes. Finally, we evaluated the aggregated human genetic evidence and theoretical druggability of the prioritized Huntington's disease modifier genes, including characteristics recently associated with clinical trial stoppage due to safety concerns (i.e. human genetic constraint, number of interacting partners and RNA tissue expression specificity). In total, we annotated and assessed nine robust candidate Huntington's disease modifier genes. Notably, we detected a high correlation (<i>R</i> ² = 0.78) in top age-of-onset genome-wide association study hits across repeat expansion disorders, emphasizing cross-disorder relevance. Clinical genetic repositories analysis showed DNA repair genes, such as <i>MLH1</i>, <i>PMS2</i> and <i>MSH3</i>, are associated with cancer phenotypes, suggesting potential limitations as drug targets. <i>LIG1</i> and <i>RRM2B</i> were both associated with neurofibrillary tangles, which may provide a link to a potential role in mHTT aggregates, while <i>MSH3</i> was associated with several cortical morphology-related traits relevant to Huntington's disease. Finally, human genetic evidence and theoretical druggability analyses prioritized and ranked modifier genes, with <i>PMS1</i> exhibiting the most favourable profile. Notably, <i>HTT</i> itself ranked poorly as a theoretical drug target, emphasizing the importance of exploring modifier-based alternative targets. In conclusion, our study highlights the importance of human genomic information to prioritize Huntington's disease modifier genes as drug targets, providing a basis for future therapeutic development in Huntington's disease and other repeat expansion disorders.