Year: 2019
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized examination of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown. METHODS: We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by 1) constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders and of intelligence and 2) testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n = 5160) of patients with HD. RESULTS: Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence. CONCLUSIONS: Polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.
Source: Biological Psychiatry
Authors: Natalie Ellis, Amelia Tee, Branduff McAllister, Thomas Massey, Duncan McLauchlan, Timothy Stone, Kevin Correia, Jacob Loupe, Kyung-Hee Kim, Douglas Barker, Eun Pyo Hong, Michael J. Chao, Jeffrey D. Long, Diane Lucente, Jean Paul G. Vonsattel, Ricardo Mouro Pinto, Kawther Abu Elneel, Eliana Marisa Ramos, Jayalakshmi Srinidhi Mysore, Tammy Gillis, Vanessa C. Wheeler, Christopher Medway, Lynsey Hall, Seung Kwak, Cristina Sampaio, Marc Ciosi, Alastair Maxwell, Afroditi Chatzi, Darren G. Monckton, Michael Orth, G. Bernhard Landwehrmeyer, Jane S. Paulsen, Ira Shoulson, Richard H. Myers, Erik van Duijn, Hugh Rickards, Marcy E. MacDonald, Jong-min Lee, James F. Gusella, Lesley Jones, Peter Holmans
Institutions: University Hospital of Wales, Cardiff University, Medical Research Council, University College London, Massachusetts General Hospital, HudsonAlpha Institute for Biotechnology, Harvard University, University of Iowa, University of Iowa Health Care, Columbia University Irving Medical Center, CHDI Foundation, University of Glasgow, Universität Ulm, University of Rochester Medicine, University of Rochester, Boston University, Leiden University Medical Center, Birmingham and Solihull Mental Health NHS Foundation Trust, University of Birmingham, Broad Institute, Columbia University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,300
Funders: Huntington's Disease Society of America, GlaxoSmithKline, Roche, CHDI Foundation, Teva Pharmaceutical Industries, Alnylam Pharmaceuticals, UCB, EU Joint Programme – Neurodegenerative Disease Research, European Huntington's Disease Network, European Commission, Cardiff University, Ipsen Fund, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, School of Medicine, CHA University, Universität Ulm, H. Lundbeck A/S, National Institutes of Health, Allergan, Roche Products, Medical Research Council, Seventh Framework Programme, School of Chemistry, Cardiff University, National Institute of Neurological Disorders and Stroke, UCB Pharma
Awards: Neurobiological Predictors of Huntington's Disease, Statistical disease modeling and clinimetrics to prepare for preventive trials in huntington disease, Disease-Modifying Genes in Huntington's Disease, G3056391515, Genetic modifiers of Predict-HD phenotypes, Understanding the role of DNA repair in Huntington's Disease pathogenesis: towards new therapeutic targets, MRC Centre for Neuropsychiatric Genetics and Genomics, Accelerating translational research through Cardiff University’s Clinical Innovation pipeline, Huntington's Disease Center Without Walls, G9000104229, Preparing for preventive clinical trials in Huntington's disease, Huntington's Disease Repeat Instability and Pathogenesis
OpenAlex ID: W2995952644