한빛사논문
- 조회574
Jong-Min Lee1,2,3, Yuan Huang4, Michael Orth5, Tammy Gillis1, Jacqueline Siciliano1, Eunpyo Hong1, Jayalakshmi Srinidhi Mysore1, Diane Lucente1, Vanessa C. Wheeler1,2, Ihn Sik Seong1,2, Zachariah L. McLean1,2,3, James A. Mills6, Branduff McAllister7, Sergey V. Lobanov7, Thomas H. Massey7, Marc Ciosi8, G. Bernhard Landwehrmeyer9, Jane S. Paulsen10, E. Ray Dorsey11, Ira Shoulson11, Cristina Sampaio12, Darren G. Monckton8, Seung Kwak12, Peter Holmans7, Lesley Jones7, Marcy E. MacDonald1,2,3, Jeffrey D. Long6, James F. Gusella1,3,13,*
1Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
2Department of Neurology, Harvard Medical School, Boston, MA 02115, USA
3Medical and Population Genetics Program, the Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
4Department of Biostatistics, School of Public Health, Yale University, New Haven, CT 06511, USA
5Department of Old Age Psychiatry and Psychotherapy, Bern University, 3000 Bern 60, Switzerland
6Department of Psychiatry, Carver College of Medicine, and Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA 52242, USA
7Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK
8Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K
9Department of Neurology, University of Ulm, Ulm 89081, Germany
10Department of Neurology, University of Wisconsin, Madison, 1685 Highland Ave, Madison, WI 53705, USA
11Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA
12CHDI Management/CHDI Foundation, Princeton, NJ 08540, USA
13Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
*Corresponding author.
Abstract
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.
논문정보
- Research article
- 2022년 03월 (BRIC 등록일 2022-03-30)
- 국외 연구진
- 생명과학 > 유전학
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