Acta Neuropathologica Communications (Jan 2020)
Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies
- Tatiana Orme,
- Dena Hernandez,
- Owen A. Ross,
- Celia Kun-Rodrigues,
- Lee Darwent,
- Claire E. Shepherd,
- Laura Parkkinen,
- Olaf Ansorge,
- Lorraine Clark,
- Lawrence S. Honig,
- Karen Marder,
- Afina Lemstra,
- Ekaterina Rogaeva,
- Peter St. George-Hyslop,
- Elisabet Londos,
- Henrik Zetterberg,
- Kevin Morgan,
- Claire Troakes,
- Safa Al-Sarraj,
- Tammaryn Lashley,
- Janice Holton,
- Yaroslau Compta,
- Vivianna Van Deerlin,
- John Q. Trojanowski,
- Geidy E. Serrano,
- Thomas G. Beach,
- Suzanne Lesage,
- Douglas Galasko,
- Eliezer Masliah,
- Isabel Santana,
- Pau Pastor,
- Pentti J. Tienari,
- Liisa Myllykangas,
- Minna Oinas,
- Tamas Revesz,
- Andrew Lees,
- Brad F. Boeve,
- Ronald C. Petersen,
- Tanis J. Ferman,
- Valentina Escott-Price,
- Neill Graff-Radford,
- Nigel J. Cairns,
- John C. Morris,
- Stuart Pickering-Brown,
- David Mann,
- Glenda Halliday,
- David J. Stone,
- Dennis W. Dickson,
- John Hardy,
- Andrew Singleton,
- Rita Guerreiro,
- Jose Bras
Affiliations
- Tatiana Orme
- UK Dementia Research Institute at UCL and Department of Molecular Neuroscience, Institute of Neurology, University College London
- Dena Hernandez
- Laboratory of Neurogenetics, National Institutes on Aging, NIH
- Owen A. Ross
- Department of Neuroscience, Mayo Clinic
- Celia Kun-Rodrigues
- Center for Neurodegenerative Science, Van Andel Research Institute
- Lee Darwent
- UK Dementia Research Institute at UCL and Department of Molecular Neuroscience, Institute of Neurology, University College London
- Claire E. Shepherd
- Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales
- Laura Parkkinen
- Nuffield Department of Clinical Neurosciences, Oxford Parkinson’s Disease Centre, University of Oxford
- Olaf Ansorge
- Nuffield Department of Clinical Neurosciences, Oxford Parkinson’s Disease Centre, University of Oxford
- Lorraine Clark
- Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology and Neurology, Columbia University Medical Center
- Lawrence S. Honig
- Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology and Neurology, Columbia University Medical Center
- Karen Marder
- Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology and Neurology, Columbia University Medical Center
- Afina Lemstra
- Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center
- Ekaterina Rogaeva
- Department of Medicine, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto
- Peter St. George-Hyslop
- Department of Medicine, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto
- Elisabet Londos
- Clinical Memory Research Unit, Institution of Clinical Sciences Malmö, Lund University
- Henrik Zetterberg
- UK Dementia Research Institute at UCL and Department of Molecular Neuroscience, Institute of Neurology, University College London
- Kevin Morgan
- Human Genetics, School of Life Sciences, University of Nottingham
- Claire Troakes
- Department of Basic and Clinical Neuroscience and Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Safa Al-Sarraj
- Department of Basic and Clinical Neuroscience and Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Tammaryn Lashley
- Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology
- Janice Holton
- Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology
- Yaroslau Compta
- Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology
- Vivianna Van Deerlin
- Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania
- John Q. Trojanowski
- Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania
- Geidy E. Serrano
- Banner Sun Health Research Institute
- Thomas G. Beach
- Banner Sun Health Research Institute
- Suzanne Lesage
- Sorbonne Université, Université Pierre et Marie Curie-Paris 06, Inserm, Centre National de la Reserche Scientifique, and Institute du Cerveau et de la Moelle épinière
- Douglas Galasko
- Assistance Publique Hôpitaux de Paris, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique
- Eliezer Masliah
- Division of Neurosciences and Laboratory of Neurogenetics, National Institute on Aging/NIH
- Isabel Santana
- Neurology Service, University of Coimbra Hospital
- Pau Pastor
- Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona
- Pentti J. Tienari
- Translational Immunology, Research Programs Unit, Department of Neurology, Helsinki University Hospital, University of Helsinki
- Liisa Myllykangas
- Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital
- Minna Oinas
- Department of Neuropathology and Neurosurgery, Helsinki University Hospital and University of Helsinki
- Tamas Revesz
- Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology
- Andrew Lees
- Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology
- Brad F. Boeve
- Neurology Department, Mayo Clinic
- Ronald C. Petersen
- Department of Psychiatry and Department of Psychology, Mayo Clinic
- Tanis J. Ferman
- Department of Psychiatry and Department of Psychology, Mayo Clinic
- Valentina Escott-Price
- UK Dementia Research Institute at Cardiff and MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University
- Neill Graff-Radford
- Department of Neurology, Mayo Clinic
- Nigel J. Cairns
- Department of Neurology, Washington University School of Medicine
- John C. Morris
- Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester
- Stuart Pickering-Brown
- Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester
- David Mann
- Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester
- Glenda Halliday
- Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales
- David J. Stone
- Genetics and Pharmacogenomics, Merck & Co., Inc.
- Dennis W. Dickson
- Department of Neuroscience, Mayo Clinic
- John Hardy
- UK Dementia Research Institute at UCL and Department of Molecular Neuroscience, Institute of Neurology, University College London
- Andrew Singleton
- Laboratory of Neurogenetics, National Institutes on Aging, NIH
- Rita Guerreiro
- Center for Neurodegenerative Science, Van Andel Research Institute
- Jose Bras
- Center for Neurodegenerative Science, Van Andel Research Institute
- DOI
- https://doi.org/10.1186/s40478-020-0879-z
- Journal volume & issue
-
Vol. 8,
no. 1
pp. 1 – 11
Abstract
Abstract Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.
