title: Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies.
abstract: Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
authors: Department of Molecular Neuroscience, j.bras@ucl.ac.uk.
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authors: Department of Molecular Neuroscience.
authors: Rita
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authors: Department of Molecular Neuroscience.
authors: Lee
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authors: Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
authors: Laura
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authors: Parkkinen
authors: Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
authors: Olaf
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authors: Ansorge
authors: MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK.
authors: Valentina
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authors: Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, USA.
authors: Dena G
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authors: Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, USA.
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authors: Taub Institute for Alzheimer Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY, USA.
authors: Lawrence S
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authors: Taub Institute for Alzheimer Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY, USA.
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authors: Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
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authors: Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
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authors: Ekaterina
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authors: Rogaeva
authors: Department of Medicine, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada, Cambridge Institute for Medical Research, and Cambridge National Institute of Health Research Biomedical Research Unit in Dementia, University of Cambridge, Cambridge CB2 0XY, UK.
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authors: Clinical Memory Research Unit, Institute Clinical Sciences Malmö, Lund University, Sweden.
authors: Elisabet
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authors: Department of Molecular Neuroscience, Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors: Henrik
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authors: Zetterberg
authors: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain, Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain, CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.
authors: Sara
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authors: Ortega-Cubero
authors: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain, Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain, CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.
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authors: Graff-Radford
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
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authors: Translation Cell Sciences - Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
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authors: Barber
authors: Translation Cell Sciences - Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
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authors: Translation Cell Sciences - Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
authors: Kristelle
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authors: Brown
authors: Translation Cell Sciences - Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
authors: Kevin
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authors: Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, Center of Neurology, University of Tuebingen, and DZNE, German Center for Neurodegenerative Diseases, Tuebingen, Germany.
authors: Walter
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authors: Maetzler
authors: Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, Center of Neurology, University of Tuebingen, and DZNE, German Center for Neurodegenerative Diseases, Tuebingen, Germany.
authors: Daniela
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authors: Berg
authors: MRC London Neurodegenerative Diseases Brain Bank, Department of Clinical Neuroscience, King's College London, Institute of Psychiatry, London, UK.
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authors: Troakes
authors: MRC London Neurodegenerative Diseases Brain Bank, Department of Clinical Neuroscience, King's College London, Institute of Psychiatry, London, UK.
authors: Safa
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authors: Al-Sarraj
authors: Queen Square Brain Bank, Department of Molecular Neuroscience, and.
authors: Tammaryn
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authors: Lashley
authors: Queen Square Brain Bank, Department of Molecular Neuroscience, and Parkinson's disease and Movement Disorders Unit, Neurology Service, IDIBAPS, CIBERNED, Hospital Clínic, Barcelona, Catalonia, Spain.
authors: Yaroslau
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authors: Compta
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authors: Revesz
authors: Queen Square Brain Bank, Department of Molecular Neuroscience, and.
authors: Andrew
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authors: Lees
authors: Knight Alzheimer's Disease Research Center and Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
authors: Nigel
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authors: Cairns
authors: Neuroscience Research Australia, Sydney, Australia, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors: Glenda M
authors: GM
authors: Halliday
authors: Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK and.
authors: David
authors: D
authors: Mann
authors: Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK and.
authors: Stuart
authors: S
authors: Pickering-Brown
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Dennis W
authors: DW
authors: Dickson
authors: Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, USA.
authors: Andrew
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mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D006801:Humans; D020961:Lewy Body Disease / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051907:Lysosomal Membrane Proteins / Q000235:genetics*; D008247:Lysosomes / Q000473:pathology*; D008297:Male; D010300:Parkinson Disease / Q000209:etiology / Q000235:genetics / Q000473:pathology; D051116:Receptors, Scavenger / Q000235:genetics*; D012307:Risk Factors; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D001057:Apolipoproteins E; D051907:Lysosomal Membrane Proteins; D051116:Receptors, Scavenger; C074299:SCARB2 protein, human; C497604:SNCA protein, human; D051844:alpha-Synuclein