부산대학교 도서관

Keywords Huntington disease; CAG repeat; trinucleotide repeat; genetic modifier; age at onset; somatic expansion; DNA maintenance; DNA repair; polyglutamine disease; disease modification Summary 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. Author Affiliation: (1) Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA (2) Department of Neurology, Harvard Medical School, Boston, MA 02115, USA (3) Medical and Population Genetics Program, the Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA (4) Department of Biostatistics, School of Public Health, Yale University, New Haven, CT 06511, USA (5) Department of Old Age Psychiatry and Psychotherapy, Bern University, 3000 Bern 60, Switzerland (6) Department of Psychiatry, Carver College of Medicine, and Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA 52242, USA (7) Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK (8) Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K (9) Department of Neurology, University of Ulm, Ulm 89081, Germany (10) Department of Neurology, University of Wisconsin, Madison, 1685 Highland Ave, Madison, WI 53705, USA (11) Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA (12) CHDI Management/CHDI Foundation, Princeton, NJ 08540, USA (13) Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA * Corresponding author Article History: Received 30 December 2021; Accepted 1 March 2022 (miscellaneous) Published: March 23, 2022 Byline: Jong-Min Lee (1,2,3), Yuan Huang (4), Michael Orth (5), Tammy Gillis (1), Jacqueline Siciliano (1), Eunpyo Hong (1), Jayalakshmi Srinidhi Mysore (1), Diane Lucente (1), Vanessa C. Wheeler (1,2), Ihn Sik Seong (1,2), Zachariah L. McLean (1,2,3), James A. Mills (6), Branduff McAllister (7), Sergey V. Lobanov (7), Thomas H. Massey (7), Marc Ciosi (8), G. Bernhard Landwehrmeyer (9), Jane S. Paulsen (10), E. Ray Dorsey (11), Ira Shoulson (11), Cristina Sampaio (12), Darren G. Monckton (8), Seung Kwak (12), Peter Holmans (7), Lesley Jones (7), Marcy E. MacDonald (1,2,3), Jeffrey D. Long (6), James F. Gusella [gusella@helix.mgh.harvard.edu] (1,3,13,*)