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Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into the complex genetic architecture

Ruth Chia, Marya S. Sabir, Sara Bandres-Ciga, Sara Saez-Atienzar, Regina H. Reynolds, Emil Gustavsson, Ronald L. Walton, Sarah Ahmed, Coralie Viollet, Jinhui Ding, Mary B. Makarious, Monica Diez-Fairen, Makayla K. Portley, Zalak Shah, Yevgeniya Abramzon, Dena G. Hernandez, Cornelis Blauwendraat, David J. Stone, John Eicher, Laura Parkkinen, Olaf Ansorge, Lorraine Clark, Lawrence S. Honig, Karen Marder, Afina Lemstra, Peter St George-Hyslop, Elisabet Londos, Kevin Morgan, Tammaryn Lashley, Thomas T. Warner, Zane Jaunmuktane, Douglas Galasko, Isabel Santana, Pentti J. Tienari, Liisa Myllykangas, Minna Oinas, Nigel J. Cairns, John C. Morris, Glenda M. Halliday, Vivianna M. Van Deerlin, John Q. Trojanowski, Maurizio Grassano, Andrea Calvo, Gabriele Mora, Antonio Canosa, Gianluca Floris, Ryan C. Bohannan, Francesca Brett, Ziv Gan-Or, Joshua T. Geiger, Anni Moore, Patrick May, Rejko Krüger, David Goldstein, Grisel Lopez, Nahid Tayebi, Ellen Sidransky, the Fox Investigation for New Discovery of Biomarkers; The American Genome Center; Lucy Norcliffe-Kaufmann, Jose-Alberto Palma, Horacio Kaufmann, Vikram Shakkottai, Matthew Perkins, Kathy L. Newell, Thomas Gasser, Claudia Schulte, Francesco Landi, Erika Salvi, Daniele Cusi, Eliezer Masliah, Ronald C. Kim, Chad A. Caraway, Ed Monuki, Maura Brunetti, Ted M. Dawson, Liana S. Rosenthal, Marilyn S. Albert, Olga Pletnikova, Juan C. Troncoso, Margaret E. Flanagan, Qinwen Mao, Eileen H. Bigio, Eloy Rodríguez-Rodríguez, Jon Infante, Carmen Lage, Isabel González-Aramburu, Pascual Sanchez-Juan, Bernardino Ghetti, Julia Keith, Sandra E. Black, Mario Masellis, Ekaterina Rogaeva, Charles Duyckaerts, Alexis Brice, Suzanne Lesage, Georgia Xiromerisiou, Matthew J. Barrett, Bension S. Tilley, Steve Gentleman, Giancarlo Logroscino, Geidy E. Serrano, Thomas G. Beach, Ian G. McKeith, Alan J. Thomas, Johannes Attems, Christopher M. Morris, Laura Palmer, Seth Love, Claire Troakes, Safa Al-Sarraj, Angela K. Hodges, Dag Aarsland, Gregory Klein, Scott M. Kaiser, Randy Woltjer, Pau Pastor, Lynn M. Bekris, James Leverenz, Lilah M. Besser, Amanda Kuzma, Alan E. Renton, Alison Goate, David A. Bennett, Clemens R. Scherzer, Huw R. Morris, Raffaele Ferrari, Diego Albani, Stuart Pickering- Brown, Kelley Faber, Walter Kukull, Estrella Morenas-Rodriguez, Alberto Lleó, Juan Fortea, Daniel Alcolea, Jordi Clarimon, Michael A. Nalls, Luigi Ferrucci, Susan M. Resnick, Toshiko Tanaka, Tatiana M. Foroud, Neill R. Graff-Radford, Zbigniew K. Wszolek, Tanis Ferman, Bradley F. Boeve, John A. Hardy, Eric Topol, Ali Torkamani, Andrew B. Singleton, Mina Ryten, Dennis Dickson, Adriano Chiò, Owen A. Ross, J. Raphael Gibbs, Clifton L. Dalgard, Bryan J. Traynor, View ORCID ProfileSonja W. Scholz
doi: https://doi.org/10.1101/2020.07.06.185066
Ruth Chia
1Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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Marya S. Sabir
2Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
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Sara Bandres-Ciga
3Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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Sara Saez-Atienzar
1Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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Regina H. Reynolds
4Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK
5NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK
6Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, London, UK
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Emil Gustavsson
5NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK
6Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, London, UK
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Ronald L. Walton
7Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
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Sarah Ahmed
2Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
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Coralie Viollet
8Department of Anatomy, Physiology and Genetics, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
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Jinhui Ding
9Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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Mary B. Makarious
2Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
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Monica Diez-Fairen
10Memory and Movement Disorders Units, Department of Neurology, University Hospital Mutua de Terrassa, Barcelona, Spain
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Makayla K. Portley
2Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
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Zalak Shah
2Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
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Yevgeniya Abramzon
1Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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Dena G. Hernandez
3Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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Cornelis Blauwendraat
3Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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David J. Stone
11Cerevel Therapeutics, Boston, MA, USA
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John Eicher
12Genetics and Pharmacogenomics, Merck & Co., Inc., West Point, PA, USA
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Laura Parkkinen
13Nuffield Department of Clinical Neurosciences, Oxford Parkinson’s Disease Centre, University of Oxford, Oxford, UK
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Olaf Ansorge
13Nuffield Department of Clinical Neurosciences, Oxford Parkinson’s Disease Centre, University of Oxford, Oxford, UK
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Lorraine Clark
14Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
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Lawrence S. Honig
14Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
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Karen Marder
14Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
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Afina Lemstra
15Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, Amsterdam, Netherlands
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Peter St George-Hyslop
16Department of Neurosciences, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, UK
17Department of Medicine, University of Toronto, Toronto, ON, Canada
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Elisabet Londos
18Clinical Memory Research Unit, Institution of Clinical Sciences Malmo, Lund University, Lund, Sweden
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Kevin Morgan
19Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK
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Tammaryn Lashley
4Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK
20Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK
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Thomas T. Warner
20Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK
21Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK
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Zane Jaunmuktane
20Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK
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Douglas Galasko
22Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA
23Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA
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Isabel Santana
24Neurology Service, University of Coimbra Hospital, Coimbra, Portugal
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Pentti J. Tienari
25Translational Immunology, Research Programs Unit, University of Helsinki, Helsinki, Finland
26Department of Neurology, Helsinki University Hospital, Helsinki, Finland
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Liisa Myllykangas
27Department of Pathology, Medicum, University of Helsinki, Helsinki, Finland
28HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
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Minna Oinas
29Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland
30Department of Clinical Medicine, Faculty of Health, UiT The Arctic University of Norway, Tromsø, Norway
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Nigel J. Cairns
31Knight Alzheimer’s Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA
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John C. Morris
31Knight Alzheimer’s Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA
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Glenda M. Halliday
32Neuroscience Research Australia, Sydney, NSW, Australia
33School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
34Brain and Mind Centre, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
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Vivianna M. Van Deerlin
35Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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John Q. Trojanowski
35Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Maurizio Grassano
36“Rita Levi Montalcini” Department of Neuroscience, University of Turin, Turin, Italy
1Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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Andrea Calvo
36“Rita Levi Montalcini” Department of Neuroscience, University of Turin, Turin, Italy
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Gabriele Mora
37Istituti Clinici Scientifici Maugeri, IRCCS, Milan, Italy
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Antonio Canosa
36“Rita Levi Montalcini” Department of Neuroscience, University of Turin, Turin, Italy
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Gianluca Floris
38Department of Neurology, University Hospital of Cagliari, Cagliari, Italy
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Ryan C. Bohannan
39Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA
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Francesca Brett
40Dublin Brain Bank, Neuropathology Department, Beaumont Hospital, Dublin, Ireland
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Ziv Gan-Or
41Montreal Neurological Institute and Hospital, Department of Neurology & Neurosurgery, McGill University, Montreal, QC, Canada
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Joshua T. Geiger
2Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
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Anni Moore
9Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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Patrick May
42Luxembourg Center for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
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Rejko Krüger
42Luxembourg Center for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
43Luxembourg Institute of Health (LIH), Strassen, Luxembourg
44Centre Hospitalier de Luxembourg (CHL), Luxembourg City, Luxembourg
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David Goldstein
45Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
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Grisel Lopez
46Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA
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Nahid Tayebi
46Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA
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Ellen Sidransky
46Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA
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47Department of Neurology, New York University School of Medicine, New York, NY, USA
Jose-Alberto Palma
47Department of Neurology, New York University School of Medicine, New York, NY, USA
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Horacio Kaufmann
47Department of Neurology, New York University School of Medicine, New York, NY, USA
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Vikram Shakkottai
48Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA
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Matthew Perkins
49Michigan Brain Bank, University of Michigan Medical School, Ann Arbor, MI, USA
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Kathy L. Newell
50Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
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Thomas Gasser
51Department of Neurodegenerative Diseases and German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany
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Claudia Schulte
51Department of Neurodegenerative Diseases and German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany
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Francesco Landi
52Department of Gerontology and Geriatrics, Catholic University of the Sacred Heart, Rome, Italy
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Erika Salvi
53Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
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Daniele Cusi
54Bio4Dreams-Business Nursery for Life, Milan, Italy
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Eliezer Masliah
55Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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Ronald C. Kim
56Department of Neuropathology, School of Medicine, University of California Irvine, Irvine, CA, USA
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Chad A. Caraway
57Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA
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Ed Monuki
58Department of Pathology & Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA
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Maura Brunetti
36“Rita Levi Montalcini” Department of Neuroscience, University of Turin, Turin, Italy
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Ted M. Dawson
59Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA
60Neuroregeneration and Stem Cell Programs, Institute of Cell Engineering, Johns Hopkins University Medical Center, Baltimore, MD, USA
61Department of Pharmacology and Molecular Science, Johns Hopkins University Medical Center, Baltimore, MD, USA
62Solomon H. Snyder Department of Neuroscience, Johns Hopkins University Medical Center, Baltimore, MD, USA
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Liana S. Rosenthal
59Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA
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Marilyn S. Albert
59Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA
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Olga Pletnikova
63Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA
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Juan C. Troncoso
63Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA
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Margaret E. Flanagan
64Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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Qinwen Mao
64Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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Eileen H. Bigio
64Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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Eloy Rodríguez-Rodríguez
65Neurology Service, University Hospital Marqués de Valdecilla-IDIVAL-UC-CIBERNED, Santander, Spain
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Jon Infante
65Neurology Service, University Hospital Marqués de Valdecilla-IDIVAL-UC-CIBERNED, Santander, Spain
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Carmen Lage
65Neurology Service, University Hospital Marqués de Valdecilla-IDIVAL-UC-CIBERNED, Santander, Spain
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Isabel González-Aramburu
65Neurology Service, University Hospital Marqués de Valdecilla-IDIVAL-UC-CIBERNED, Santander, Spain
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Pascual Sanchez-Juan
65Neurology Service, University Hospital Marqués de Valdecilla-IDIVAL-UC-CIBERNED, Santander, Spain
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Bernardino Ghetti
50Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
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Julia Keith
66Department of Anatomical Pathology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
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Sandra E. Black
67Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
68Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada
69Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
70Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada
71LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada
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Mario Masellis
72Cognitive & Movement Disorders Clinic, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
73Department of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada
70Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada
71LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada
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Ekaterina Rogaeva
74Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada
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Charles Duyckaerts
75Department of Neuropathology Escourolle, Paris Brain Institute, Sorbonne Universites, Paris, France
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Alexis Brice
76Paris Brain Institute, Sorbonne Universites, Paris, France
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Suzanne Lesage
76Paris Brain Institute, Sorbonne Universites, Paris, France
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Georgia Xiromerisiou
77Department of Neurology, University Hospital of Larissa, University of Thessalia, Larissa, Greece
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Matthew J. Barrett
78Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA
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Bension S. Tilley
79Neuropathology Unit, Department of Brain Sciences, Imperial College London, London, UK
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Steve Gentleman
79Neuropathology Unit, Department of Brain Sciences, Imperial College London, London, UK
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Giancarlo Logroscino
80Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari “Aldo Moro”, Bari, Italy
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Geidy E. Serrano
81Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA
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Thomas G. Beach
81Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA
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Ian G. McKeith
82Mental Health, Newcastle Brain Tissue Resource, Translational and Clinical Research Institute, Biomedical Research Building, Newcastle University, Newcastle upon Tyne, UK
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Alan J. Thomas
82Mental Health, Newcastle Brain Tissue Resource, Translational and Clinical Research Institute, Biomedical Research Building, Newcastle University, Newcastle upon Tyne, UK
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Johannes Attems
82Mental Health, Newcastle Brain Tissue Resource, Translational and Clinical Research Institute, Biomedical Research Building, Newcastle University, Newcastle upon Tyne, UK
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Christopher M. Morris
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94Ronald M. Loeb Center for Alzheimer’s Disease, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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95Ronald M. Loeb Center for Alzheimer’s Disease, Nash Family Department of Neuroscience, Department of Genetics and Genomic Sciences, and Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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87Rush Alzheimer’s Disease Center, Rush University, Chicago, IL, USA
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96Precision Neurology Program, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA
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97Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, University College London, London, UK
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Raffaele Ferrari
4Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK
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98Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
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99Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
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100Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
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101National Alzheimer’s Coordinating Center (NACC), University of Washington, Seattle, WA, USA
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Estrella Morenas-Rodriguez
102Biomedizinisches Centrum (BMC), Biochemie, Ludwig-Maximilians-Universität München & Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Munich, Germany
103Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
104The Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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Alberto Lleó
103Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
104The Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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103Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
104The Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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103Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
104The Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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105Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
106Data Tecnica International, Glen Echo, MD, USA
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107Longitudinal Studies Section, National Institute on Aging, Baltimore, MD, USA
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108Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA
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107Longitudinal Studies Section, National Institute on Aging, Baltimore, MD, USA
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100Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
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109Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
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109Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
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110Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA
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4Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK
112UK Dementia Research Institute of UCL, UCL Institute of Neurology, University College London, London, UK
21Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK
113UCL Movement Disorders Centre, University College London, London, UK
114Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China
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115Scripps Research Translational Institute, Scripps Research, La Jolla, CA, USA
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3Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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5NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK
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7Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
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36“Rita Levi Montalcini” Department of Neuroscience, University of Turin, Turin, Italy
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117Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy
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Owen A. Ross
7Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
118Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA
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9Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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Clifton L. Dalgard
8Department of Anatomy, Physiology and Genetics, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
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Bryan J. Traynor
1Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
59Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA
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Sonja W. Scholz
2Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
59Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA
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Abstract

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Competing Interest Statement

Thomas G. Beach is a consultant for Prothena, Vivid Genomics and Avid Radiopharmaceuticals. He is a scientific advisory board member for Vivid Genomics. John A. Hardy, Huw R. Morris, Stuart Pickering-Brown, Andrew B. Singleton, and Bryan J. Traynor hold US, EU and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. Michael A. Nalls is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA; as a possible conflict of interest Dr. Nalls also consults for Neuron23 Inc., Lysosomal Therapeutics Inc., Illumina Inc., the Michael J. Fox Foundation and Vivid Genomics among others. Jose A. Palma is an editorial board member of Movement Disorders, Parkinsonism & Related Disorders, BMC Neurology, and Clinical Autonomic Research. Bradley F. Boeve, James Leverenz, and Sonja W. Scholz serve on the Scientific Advisory Council of the Lewy Body Dementia Association. Sonja W. Scholz is an editorial board member for the Journal of Parkinson's Disease. Bryan J. Traynor is an editorial board member for JAMA Neurology; Journal of Neurology, Neurosurgery, and Psychiatry; Brain; and Neurobiology of Aging. Zbigniew K. Wszolek serves as a principal investigator or co-principal investigator on Abbvie, Inc. (M15-562 and M15-563), Biogen, Inc. (228PD201) grant, and Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301). Zbigniew K. Wszolek serves as the principal investigator of the Mayo Clinic American Parkinson Disease Association (APDA) Information and Referral Center, and as co-principal investigator of the Mayo Clinic APDA Center for Advanced Research. All other authors report no competing interests.

Footnotes

  • ↵# These authors are joint last authors.

  • https://www.eqtlgen.org/cis-eqtls.html

  • http://resource.psychencode.org/

  • https://www.gtexportal.org/home/

  • http://portal.brain-map.org/atlases-and-data

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into the complex genetic architecture
Ruth Chia, Marya S. Sabir, Sara Bandres-Ciga, Sara Saez-Atienzar, Regina H. Reynolds, Emil Gustavsson, Ronald L. Walton, Sarah Ahmed, Coralie Viollet, Jinhui Ding, Mary B. Makarious, Monica Diez-Fairen, Makayla K. Portley, Zalak Shah, Yevgeniya Abramzon, Dena G. Hernandez, Cornelis Blauwendraat, David J. Stone, John Eicher, Laura Parkkinen, Olaf Ansorge, Lorraine Clark, Lawrence S. Honig, Karen Marder, Afina Lemstra, Peter St George-Hyslop, Elisabet Londos, Kevin Morgan, Tammaryn Lashley, Thomas T. Warner, Zane Jaunmuktane, Douglas Galasko, Isabel Santana, Pentti J. Tienari, Liisa Myllykangas, Minna Oinas, Nigel J. Cairns, John C. Morris, Glenda M. Halliday, Vivianna M. Van Deerlin, John Q. Trojanowski, Maurizio Grassano, Andrea Calvo, Gabriele Mora, Antonio Canosa, Gianluca Floris, Ryan C. Bohannan, Francesca Brett, Ziv Gan-Or, Joshua T. Geiger, Anni Moore, Patrick May, Rejko Krüger, David Goldstein, Grisel Lopez, Nahid Tayebi, Ellen Sidransky, the Fox Investigation for New Discovery of Biomarkers; The American Genome Center; Lucy Norcliffe-Kaufmann, Jose-Alberto Palma, Horacio Kaufmann, Vikram Shakkottai, Matthew Perkins, Kathy L. Newell, Thomas Gasser, Claudia Schulte, Francesco Landi, Erika Salvi, Daniele Cusi, Eliezer Masliah, Ronald C. Kim, Chad A. Caraway, Ed Monuki, Maura Brunetti, Ted M. Dawson, Liana S. Rosenthal, Marilyn S. Albert, Olga Pletnikova, Juan C. Troncoso, Margaret E. Flanagan, Qinwen Mao, Eileen H. Bigio, Eloy Rodríguez-Rodríguez, Jon Infante, Carmen Lage, Isabel González-Aramburu, Pascual Sanchez-Juan, Bernardino Ghetti, Julia Keith, Sandra E. Black, Mario Masellis, Ekaterina Rogaeva, Charles Duyckaerts, Alexis Brice, Suzanne Lesage, Georgia Xiromerisiou, Matthew J. Barrett, Bension S. Tilley, Steve Gentleman, Giancarlo Logroscino, Geidy E. Serrano, Thomas G. Beach, Ian G. McKeith, Alan J. Thomas, Johannes Attems, Christopher M. Morris, Laura Palmer, Seth Love, Claire Troakes, Safa Al-Sarraj, Angela K. Hodges, Dag Aarsland, Gregory Klein, Scott M. Kaiser, Randy Woltjer, Pau Pastor, Lynn M. Bekris, James Leverenz, Lilah M. Besser, Amanda Kuzma, Alan E. Renton, Alison Goate, David A. Bennett, Clemens R. Scherzer, Huw R. Morris, Raffaele Ferrari, Diego Albani, Stuart Pickering- Brown, Kelley Faber, Walter Kukull, Estrella Morenas-Rodriguez, Alberto Lleó, Juan Fortea, Daniel Alcolea, Jordi Clarimon, Michael A. Nalls, Luigi Ferrucci, Susan M. Resnick, Toshiko Tanaka, Tatiana M. Foroud, Neill R. Graff-Radford, Zbigniew K. Wszolek, Tanis Ferman, Bradley F. Boeve, John A. Hardy, Eric Topol, Ali Torkamani, Andrew B. Singleton, Mina Ryten, Dennis Dickson, Adriano Chiò, Owen A. Ross, J. Raphael Gibbs, Clifton L. Dalgard, Bryan J. Traynor, Sonja W. Scholz
bioRxiv 2020.07.06.185066; doi: https://doi.org/10.1101/2020.07.06.185066
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Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into the complex genetic architecture
Ruth Chia, Marya S. Sabir, Sara Bandres-Ciga, Sara Saez-Atienzar, Regina H. Reynolds, Emil Gustavsson, Ronald L. Walton, Sarah Ahmed, Coralie Viollet, Jinhui Ding, Mary B. Makarious, Monica Diez-Fairen, Makayla K. Portley, Zalak Shah, Yevgeniya Abramzon, Dena G. Hernandez, Cornelis Blauwendraat, David J. Stone, John Eicher, Laura Parkkinen, Olaf Ansorge, Lorraine Clark, Lawrence S. Honig, Karen Marder, Afina Lemstra, Peter St George-Hyslop, Elisabet Londos, Kevin Morgan, Tammaryn Lashley, Thomas T. Warner, Zane Jaunmuktane, Douglas Galasko, Isabel Santana, Pentti J. Tienari, Liisa Myllykangas, Minna Oinas, Nigel J. Cairns, John C. Morris, Glenda M. Halliday, Vivianna M. Van Deerlin, John Q. Trojanowski, Maurizio Grassano, Andrea Calvo, Gabriele Mora, Antonio Canosa, Gianluca Floris, Ryan C. Bohannan, Francesca Brett, Ziv Gan-Or, Joshua T. Geiger, Anni Moore, Patrick May, Rejko Krüger, David Goldstein, Grisel Lopez, Nahid Tayebi, Ellen Sidransky, the Fox Investigation for New Discovery of Biomarkers; The American Genome Center; Lucy Norcliffe-Kaufmann, Jose-Alberto Palma, Horacio Kaufmann, Vikram Shakkottai, Matthew Perkins, Kathy L. Newell, Thomas Gasser, Claudia Schulte, Francesco Landi, Erika Salvi, Daniele Cusi, Eliezer Masliah, Ronald C. Kim, Chad A. Caraway, Ed Monuki, Maura Brunetti, Ted M. Dawson, Liana S. Rosenthal, Marilyn S. Albert, Olga Pletnikova, Juan C. Troncoso, Margaret E. Flanagan, Qinwen Mao, Eileen H. Bigio, Eloy Rodríguez-Rodríguez, Jon Infante, Carmen Lage, Isabel González-Aramburu, Pascual Sanchez-Juan, Bernardino Ghetti, Julia Keith, Sandra E. Black, Mario Masellis, Ekaterina Rogaeva, Charles Duyckaerts, Alexis Brice, Suzanne Lesage, Georgia Xiromerisiou, Matthew J. Barrett, Bension S. Tilley, Steve Gentleman, Giancarlo Logroscino, Geidy E. Serrano, Thomas G. Beach, Ian G. McKeith, Alan J. Thomas, Johannes Attems, Christopher M. Morris, Laura Palmer, Seth Love, Claire Troakes, Safa Al-Sarraj, Angela K. Hodges, Dag Aarsland, Gregory Klein, Scott M. Kaiser, Randy Woltjer, Pau Pastor, Lynn M. Bekris, James Leverenz, Lilah M. Besser, Amanda Kuzma, Alan E. Renton, Alison Goate, David A. Bennett, Clemens R. Scherzer, Huw R. Morris, Raffaele Ferrari, Diego Albani, Stuart Pickering- Brown, Kelley Faber, Walter Kukull, Estrella Morenas-Rodriguez, Alberto Lleó, Juan Fortea, Daniel Alcolea, Jordi Clarimon, Michael A. Nalls, Luigi Ferrucci, Susan M. Resnick, Toshiko Tanaka, Tatiana M. Foroud, Neill R. Graff-Radford, Zbigniew K. Wszolek, Tanis Ferman, Bradley F. Boeve, John A. Hardy, Eric Topol, Ali Torkamani, Andrew B. Singleton, Mina Ryten, Dennis Dickson, Adriano Chiò, Owen A. Ross, J. Raphael Gibbs, Clifton L. Dalgard, Bryan J. Traynor, Sonja W. Scholz
bioRxiv 2020.07.06.185066; doi: https://doi.org/10.1101/2020.07.06.185066

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