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Genetic Risk Underlying Psychiatric and Cognitive Symptoms in Huntington’s Disease

Authors
  • Ellis, Natalie1
  • Tee, Amelia1
  • McAllister, Branduff2
  • Massey, Thomas2
  • McLauchlan, Duncan2, 3
  • Stone, Timothy4
  • Correia, Kevin5
  • Loupe, Jacob6
  • Kim, Kyung-Hee5, 7
  • Barker, Douglas5
  • Hong, Eun Pyo5, 7
  • Chao, Michael J.5, 7
  • Long, Jeffrey D.8, 9
  • Lucente, Diane5, 7
  • Vonsattel, Jean Paul G.10
  • Pinto, Ricardo Mouro5, 7
  • Elneel, Kawther Abu5
  • Ramos, Eliana Marisa5
  • Mysore, Jayalakshmi Srinidhi5
  • Gillis, Tammy5
  • And 21 more
  • 1 Cardiff University School of Medicine, UHW Main Building, Heath Park, Cardiff, United Kingdom
  • 2 Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom
  • 3 Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff, United Kingdom
  • 4 Department of Targeted Intervention, Division of Surgery and Interventional Science, Faculty of Medical Science, University College of London, London, United Kingdom
  • 5 Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts
  • 6 HudsonAlpha Institute for Biotechnology, Huntsville, Alabama
  • 7 Department of Neurology, Harvard Medical School, Boston, Massachusetts
  • 8 Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa
  • 9 Department of Psychiatry, Roy and Lucille Carver College of Medicine, University of Iowa, Iowa City, Iowa
  • 10 Department of Pathology and Cell Biology and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, New York
  • 11 All Wales Medical Genetics Service, Institute of Medical Genetics, University Hospital Wales, Cardiff, United Kingdom
  • 12 CHDI Foundation, Princeton, New Jersey
  • 13 Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow
  • 14 Department of Neurology, University of Ulm, Ulm, Germany
  • 15 Department of Neurology, Roy and Lucille Carver College of Medicine, University of Iowa, Iowa City, Iowa
  • 16 Department of Neurology, University of Rochester Medical Center, Rochester, New York
  • 17 Department of Neurology and Genome Science Institute, Boston University School of Medicine, Boston, Massachusetts
  • 18 Department of Psychiatry, Leiden University Medical Centre, Leiden, Netherlands
  • 19 Mental Health Care Centre Delfland, Delft, Netherlands
  • 20 National Centre for Mental Health, Birmingham and Solihull Mental Health NHS Foundation Trust, Birmingham, United Kingdom
  • 21 College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
  • 22 Medical and Population Genetics Program, the Broad Institute of M.I.T. and Harvard, Cambridge, Massachusetts
  • 23 Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts
Type
Published Article
Publication Date
May 01, 2020
Volume
87
Issue
9
Pages
857–865
Identifiers
DOI: 10.1016/j.biopsych.2019.12.010
PMID: 32087949
PMCID: PMC7156911
Source
PubMed Central
Keywords
License
Unknown

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.

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