{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T23:32:19Z","timestamp":1791588739041,"version":"4.3.4"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,1,11]],"date-time":"2025-01-11T00:00:00Z","timestamp":1736553600000},"content-version":"vor","delay-in-days":18,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008252","name":"Health Sciences Centre Foundation Winnipeg Operating Grant","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008252","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001804","name":"Canada Research Chairs Initiative","doi-asserted-by":"publisher","award":["CRC-2019-145"],"award-info":[{"award-number":["CRC-2019-145"]}],"id":[{"id":"10.13039\/501100001804","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Discovery Grant Program","award":["RGPIN-2022-04509"],"award-info":[{"award-number":["RGPIN-2022-04509"]}]},{"DOI":"10.13039\/100010318","name":"University of Manitoba","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010318","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008794","name":"Research Manitoba Studentship","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008794","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Rady Faculty of Health Sciences Student Top-Up"},{"name":"University of Manitoba Graduate Fellowship"},{"name":"Canadian Institutes of Health Research Canada Graduate Scholarship"},{"name":"Rady Faculty of Health Sciences Student Top-Up and Studentship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Huntington\u2019s disease is caused by a CAG repeat in the HTT 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\u2019s disease age-of-onset study (n = 9064), prioritizing robust candidate Huntington\u2019s 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\u2019s disease\u2013related screens, including exome studies of Huntington\u2019s disease onset and high-throughput assessments of mHTT toxicity. To confirm whether Huntington\u2019s 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\u2019s 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\u2019s disease modifier genes. Notably, we detected a high correlation (R2 = 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 MLH1, PMS2 and MSH3, are associated with cancer phenotypes, suggesting potential limitations as drug targets. LIG1 and RRM2B were both associated with neurofibrillary tangles, which may provide a link to a potential role in mHTT aggregates, while MSH3 was associated with several cortical morphology-related traits relevant to Huntington\u2019s disease. Finally, human genetic evidence and theoretical druggability analyses prioritized and ranked modifier genes, with PMS1 exhibiting the most favourable profile. Notably, HTT 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\u2019s disease modifier genes as drug targets, providing a basis for future therapeutic development in Huntington\u2019s disease and other repeat expansion disorders.<\/jats:p>","DOI":"10.1093\/braincomms\/fcae418","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T15:26:38Z","timestamp":1732029998000},"source":"Crossref","is-referenced-by-count":9,"title":["Genomic characterization of Huntington\u2019s disease genetic modifiers informs drug target tractability"],"prefix":"10.1093","volume":"7","author":[{"given":"Kevin Lucy","family":"Namuli","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba , Winnipeg, MB , R3E 0T6","place":["Canada"]},{"name":"PrairieNeuro Research Centre, Kleysen Institute for Advanced Medicine, Health Sciences Centre and Rady Faculty of Health Sciences, University of Manitoba , Winnipeg, MB , R3E 3J7","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alana N","family":"Slike","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba , Winnipeg, MB , R3E 0T6","place":["Canada"]},{"name":"PrairieNeuro Research Centre, Kleysen Institute for Advanced Medicine, Health Sciences Centre and Rady Faculty of Health Sciences, University of Manitoba , Winnipeg, MB , R3E 3J7","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mason A","family":"Hollebeke","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba , Winnipeg, MB , R3E 0T6","place":["Canada"]},{"name":"PrairieNeuro Research 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