Lee JM, Huang Y, Orth M, Gillis T, Siciliano J, Hong E, Mysore JS, Lucente D, Wheeler VC, Seong IS, McLean ZL, Mills JA, McAllister B, Lobanov SV, Massey TH, Ciosi M, Landwehrmeyer GB, Paulsen JS, Dorsey ER, Shoulson I, Sampaio C, Monckton DG, Kwak S, Holmans P, Jones L, MacDonald ME, Long JD, and Gusella JF
Genome-wide association studies (GWASs) of Huntington disease (HD) have identified six DNA maintenance gene loci (among others) as modifiers and implicated a two step-mechanism of pathogenesis: somatic instability of the causative HTT CAG repeat with subsequent triggering of neuronal damage. The largest studies have been limited to HD individuals with a rater-estimated age at motor onset. To capitalize on the wealth of phenotypic data in several large HD natural history studies, we have performed algorithmic prediction by using common motor and cognitive measures to predict age at other disease landmarks as additional phenotypes for GWASs. Combined with imputation with the Trans-Omics for Precision Medicine reference panel, predictions using integrated measures provided objective landmark phenotypes with greater power to detect most modifier loci. Importantly, substantial differences in the relative modifier signal across loci, highlighted by comparing common modifiers at MSH3 and FAN1, revealed that individual modifier effects can act preferentially in the motor or cognitive domains. Individual components of the DNA maintenance modifier mechanisms may therefore act differentially on the neuronal circuits underlying the corresponding clinical measures. In addition, we identified additional modifier effects at the PMS1 and PMS2 loci and implicated a potential second locus on chromosome 7. These findings indicate that broadened discovery and characterization of HD genetic modifiers based on additional quantitative or qualitative phenotypes offers not only the promise of in-human validated therapeutic targets but also a route to dissecting the mechanisms and cell types involved in both the somatic instability and toxicity components of HD pathogenesis., Competing Interests: Declaration of interests J.M.L. serves on the scientific advisory board of GenEdit Inc. V.C.W. is a scientific advisory board member of Triplet Therapeutics Inc., a company developing new therapeutic approaches to address triplet repeat disorders such as Huntington disease and myotonic dystrophy. Her financial interests in Triplet Therapeutics were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. She is a scientific advisory board member of LoQus23 Therapeutics Ltd and has provided paid consulting services to Acadia Pharmaceuticals Inc., Alnylam Inc., and Biogen Inc. She has also received research support from Pfizer Inc. J.A.M. is a paid consultant for PTC Therapeutics Inc. and Behavioral Diagnostics Inc. and has also been a consultant for Wave Life Sciences USA Inc. T.H.M. is an associate member of the scientific advisory board of LoQus23 Therapeutics Ltd. G.B.L. has provided consulting services, advisory board functions, clinical trial services, and lectures for Acadia, Affiris, Allergan, Alnylam, Amarin, AOP Orphan Pharmaceuticals AG, Bayer Pharma AG, Boehringer-Ingelheim, CHDI Foundation, GlaxoSmithKline, Hoffmann-LaRoche, Ipsen, ISIS (Ionis) Pharma, Lundbeck, Neurosearch Inc., Medesis, Medivation, Medtronic, NeuraMetrix, Novartis, Pfizer, Prana Biotechnology, PTC Therapeutics, Raptor, Remix, Sangamo/Shire, Sanofi-Aventis, Siena Biotech, Takeda, Temmler Pharma GmbH, Teva Pharmaceuticals and Triplet Therapeutics. J.S.P. is a paid consultant for Acadia Pharmaceuticals and Wave Life Sciences USA Inc. E.R.D. has received research support from Wave Life Sciences USA Inc. D.G.M. has been a scientific consultant and/or received honoraria/stock options from AMO Pharma, Charles River, LoQus23, Small Molecule RNA, Triplet Therapeutics, and Vertex Pharmaceuticals and held research contracts with AMO Pharma and Vertex Pharmaceuticals within the last 5 years. L.J. is a member of the scientific advisory boards of LoQus23 Therapeutics Ltd and Triplet Therapeutics Inc. and a member of the executive committee of the European Huntington Disease Network. J.D.L. is a paid advisory board member for F. Hoffmann-La Roche Ltd and UniQure, and he is a paid consultant for Triplet Therapeutics, PTC Therapeutics, and Remix Therapeutics. J.F.G. is a scientific advisory board member and has a financial interest in Triplet Therapeutics Inc. His NIH-funded project is using genetic and genomic approaches to uncover other genes that significantly influence when diagnosable symptoms emerge and how rapidly they worsen in Huntington disease. The company is developing new therapeutic approaches to address triplet repeat disorders such Huntington disease, myotonic dystrophy, and spinocerebellar ataxias. His interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. J.F.G. has also been a consultant for Wave Life Sciences USA Inc., Biogen Inc., and Pfizer Inc., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)