Neurobiology of Disease (Jul 2019)
Heritability and genetic variance of dementia with Lewy bodies
- Rita Guerreiro,
- Valentina Escott-Price,
- Dena G. Hernandez,
- Celia Kun-Rodrigues,
- Owen A. Ross,
- Tatiana Orme,
- Joao Luis Neto,
- Susana Carmona,
- Nadia Dehghani,
- John D. Eicher,
- Claire Shepherd,
- Laura Parkkinen,
- Lee Darwent,
- Michael G. Heckman,
- Sonja W. Scholz,
- Juan C. Troncoso,
- Olga Pletnikova,
- Ted Dawson,
- Liana Rosenthal,
- Olaf Ansorge,
- Jordi Clarimon,
- Alberto Lleo,
- Estrella Morenas-Rodriguez,
- Lorraine Clark,
- Lawrence S. Honig,
- Karen Marder,
- Afina Lemstra,
- Ekaterina Rogaeva,
- Peter St. George-Hyslop,
- Elisabet Londos,
- Henrik Zetterberg,
- Imelda Barber,
- Anne Braae,
- Kristelle Brown,
- Kevin Morgan,
- Claire Troakes,
- Safa Al-Sarraj,
- Tammaryn Lashley,
- Janice Holton,
- Yaroslau Compta,
- Vivianna Van Deerlin,
- Geidy E. Serrano,
- Thomas G. Beach,
- Suzanne Lesage,
- Douglas Galasko,
- Eliezer Masliah,
- Isabel Santana,
- Pau Pastor,
- Monica Diez-Fairen,
- Miquel Aguilar,
- Pentti J. Tienari,
- Liisa Myllykangas,
- Minna Oinas,
- Tamas Revesz,
- Andrew Lees,
- Brad F. Boeve,
- Ronald C. Petersen,
- Tanis J. Ferman,
- Neill Graff-Radford,
- Nigel J. Cairns,
- John C. Morris,
- Stuart Pickering-Brown,
- David Mann,
- Glenda M. Halliday,
- John Hardy,
- John Q. Trojanowski,
- Dennis W. Dickson,
- Andrew Singleton,
- David J. Stone,
- Jose Bras
Affiliations
- Rita Guerreiro
- Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK
- Valentina Escott-Price
- UK Dementia Research Institute (UK DRI) at Cardiff, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK
- Dena G. Hernandez
- Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA; German Center for Neurodegenerative Diseases (DZNE)-Tubingen, Germany
- Celia Kun-Rodrigues
- Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK
- Owen A. Ross
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
- Tatiana Orme
- Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK
- Joao Luis Neto
- Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK
- Susana Carmona
- Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK
- Nadia Dehghani
- Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK
- John D. Eicher
- Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, MA, USA
- Claire Shepherd
- Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia
- Laura Parkkinen
- Nuffield Department of Clinical Neurosciences, Oxford Parkinsons Disease Centre, University of Oxford, Oxford, UK
- Lee Darwent
- UK Dementia Research Institute (UK DRI) at UCL, London, UK
- Michael G. Heckman
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA
- Sonja W. Scholz
- Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Juan C. Troncoso
- Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Olga Pletnikova
- Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Ted Dawson
- Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Liana Rosenthal
- Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Olaf Ansorge
- Nuffield Department of Clinical Neurosciences, Oxford Parkinsons Disease Centre, University of Oxford, Oxford, UK
- Jordi Clarimon
- Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
- Alberto Lleo
- Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
- Estrella Morenas-Rodriguez
- Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
- Lorraine Clark
- Taub Institute for Alzheimer Disease and the Aging Brain, Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
- Lawrence S. Honig
- Taub Institute for Alzheimer Disease and the Aging Brain, Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
- Karen Marder
- Taub Institute for Alzheimer Disease and the Aging Brain, Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
- Afina Lemstra
- Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
- Ekaterina Rogaeva
- Tanz Centre for Research in Neurodegenerative Diseases and department of Medicine, University of Toronto, Ontario, Canada
- Peter St. George-Hyslop
- Tanz Centre for Research in Neurodegenerative Diseases and department of Medicine, University of Toronto, Ontario, Canada; Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
- Elisabet Londos
- Clinical Memory Research Unit, Institution of Clinical Sciences Malmo, Lund University, Sweden
- Henrik Zetterberg
- UK Dementia Research Institute at UCL, London UK, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK, Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden
- Imelda Barber
- Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK
- Anne Braae
- Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK
- Kristelle Brown
- Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK
- Kevin Morgan
- Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK
- Claire Troakes
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK
- Safa Al-Sarraj
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK
- Tammaryn Lashley
- Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
- Janice Holton
- Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
- Yaroslau Compta
- Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK, Movement Disorders Unit, Neurology Service, Clinical Neuroscience Institute (ICN), Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, Catalonia, Spain
- Vivianna Van Deerlin
- Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, Philadelphia, USA
- Geidy E. Serrano
- Banner Sun Health Research Institute, 10515 W Santa Fe Drive, Sun City, AZ 85351, USA
- Thomas G. Beach
- Banner Sun Health Research Institute, 10515 W Santa Fe Drive, Sun City, AZ 85351, USA
- Suzanne Lesage
- Inserm U1127, CNRS UMR7225, Sorbonne Universites, UPMC Univ Paris 06, UMR and S1127, Institut du Cerveau et de la Moelle epiniere, Paris, France
- Douglas Galasko
- Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States, Veterans Affairs San Diego Healthcare System, La Jolla, CA, United States
- Eliezer Masliah
- Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States, Department of Pathology, University of California, San Diego, La Jolla, CA, United States
- Isabel Santana
- Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine and Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Pau Pastor
- Memory Unit, Department of Neurology,University Hospital Mutua de Terrassa, University of Barcelona, Fundacion de Docencia I Recerca Mutua de Terrassa, Terrassa, Barcelona, Spain. Centro de Investigacion Biomedica en Red Enfermedades Neurdegenerativas (CIBERNED), Madrid, Spain
- Monica Diez-Fairen
- Memory Unit, Department of Neurology,University Hospital Mutua de Terrassa, University of Barcelona, Fundacion de Docencia I Recerca Mutua de Terrassa, Terrassa, Barcelona, Spain. Centro de Investigacion Biomedica en Red Enfermedades Neurdegenerativas (CIBERNED), Madrid, Spain
- Miquel Aguilar
- Memory Unit, Department of Neurology,University Hospital Mutua de Terrassa, University of Barcelona, Fundacion de Docencia I Recerca Mutua de Terrassa, Terrassa, Barcelona, Spain. Centro de Investigacion Biomedica en Red Enfermedades Neurdegenerativas (CIBERNED), Madrid, Spain
- Pentti J. Tienari
- Molecular Neurology, Research Programs Unit, University of Helsinki, Department of Neurology, Helsinki University Hospital, Helsinki, Finland
- Liisa Myllykangas
- Department of Pathology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
- Minna Oinas
- Department of Neuropathology and Neurosurgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- Tamas Revesz
- Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
- Andrew Lees
- Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
- Brad F. Boeve
- Neurology Department, Mayo Clinic, Rochester, MN, USA
- Ronald C. Petersen
- Neurology Department, Mayo Clinic, Rochester, MN, USA
- Tanis J. Ferman
- Department of Psychiatry and Department of Psychology, Mayo Clinic, Jacksonville, FL, USA
- Neill Graff-Radford
- Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
- Nigel J. Cairns
- Knight Alzheimers Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA
- John C. Morris
- Knight Alzheimers Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA
- Stuart Pickering-Brown
- Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK
- David Mann
- Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK
- Glenda M. Halliday
- Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia; Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia
- John Hardy
- Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK
- John Q. Trojanowski
- Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, Philadelphia, USA
- Dennis W. Dickson
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
- Andrew Singleton
- Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA
- David J. Stone
- Genetics and Pharmacogenomics, Merck Research Laboratories, West Point, PA, USA
- Jose Bras
- Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK; Corresponding author at: UK Dementia Research Institute at UCL, University College London, UK.
- Journal volume & issue
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Vol. 127
pp. 492 – 501
Abstract
Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.
