Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its 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 S Goldstein; Grisel Lopez; Nahid Tayebi; Ellen Sidransky; American Genome Center; Lucy Norcliffe-Kaufmann; Jose-Alberto Palma; Horacio Kaufmann; Vikram G Shakkottai; Matthew Perkins; Kathy L Newell; Thomas Gasser; Claudia Schulte; Francesco Landi; Erika Salvi; Daniele Cusi; Eliezer Masliah; Ronald C Kim; Chad A Caraway; Edwin S 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 B 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 A Kukull; Estrella Morenas-Rodriguez; Alberto Lleó; Juan Fortea; Daniel Alcolea; Jordi Clarimon; Mike 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 J Topol; Ali Torkamani; Andrew B Singleton; Mina Ryten; Dennis W Dickson; Adriano Chiò; Owen A Ross; J Raphael Gibbs; Clifton L Dalgard; Bryan J Traynor; Sonja W Scholz

doi:10.1038/s41588-021-00785-3

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

Nat Genet. 2021 Mar;53(3):294-303. doi: 10.1038/s41588-021-00785-3. Epub 2021 Feb 15.

Authors

Ruth Chia^#¹, Marya S Sabir^#², Sara Bandres-Ciga³, Sara Saez-Atienzar¹, Regina H Reynolds^{4

5

6}, Emil Gustavsson^{5

6}, Ronald L Walton⁷, Sarah Ahmed², Coralie Viollet^{8

9}, Jinhui Ding¹⁰, Mary B Makarious², Monica Diez-Fairen¹¹, Makayla K Portley², Zalak Shah², Yevgeniya Abramzon^{1

12}, Dena G Hernandez³, Cornelis Blauwendraat³, David J Stone¹³, John Eicher¹⁴, Laura Parkkinen¹⁵, Olaf Ansorge¹⁵, Lorraine Clark¹⁶, Lawrence S Honig¹⁷, Karen Marder¹⁷, Afina Lemstra¹⁸, Peter St George-Hyslop^{19

20}, Elisabet Londos²¹, Kevin Morgan²², Tammaryn Lashley^{4

23}, Thomas T Warner^{12

23}, Zane Jaunmuktane²³, Douglas Galasko^{24

25}, Isabel Santana^{26

27

28

29}, Pentti J Tienari^{30

31}, Liisa Myllykangas^{32

33}, Minna Oinas³⁴, Nigel J Cairns³⁵, John C Morris³⁵, Glenda M Halliday^{36

37

38}, Vivianna M Van Deerlin³⁹, John Q Trojanowski³⁹, Maurizio Grassano^{1

40}, Andrea Calvo^{40

41}, Gabriele Mora⁴², Antonio Canosa^{40

41}, Gianluca Floris⁴³, Ryan C Bohannan⁴⁴, Francesca Brett⁴⁵, Ziv Gan-Or⁴⁶, Joshua T Geiger², Anni Moore¹⁰, Patrick May⁴⁷, Rejko Krüger^{47

48

49}, David S Goldstein⁵⁰, Grisel Lopez⁵¹, Nahid Tayebi⁵¹, Ellen Sidransky⁵¹; American Genome Center; Lucy Norcliffe-Kaufmann⁵², Jose-Alberto Palma⁵², Horacio Kaufmann⁵², Vikram G Shakkottai⁵³, Matthew Perkins⁵⁴, Kathy L Newell⁵⁵, Thomas Gasser⁵⁶, Claudia Schulte⁵⁶, Francesco Landi⁵⁷, Erika Salvi⁵⁸, Daniele Cusi⁵⁹, Eliezer Masliah⁶⁰, Ronald C Kim⁶¹, Chad A Caraway⁶², Edwin S Monuki⁶³, Maura Brunetti⁴⁰, Ted M Dawson^{64

65

66

67}, Liana S Rosenthal⁶⁴, Marilyn S Albert⁶⁴, Olga Pletnikova^{68

69}, Juan C Troncoso⁶⁸, Margaret E Flanagan^{70

71}, Qinwen Mao^{70

71}, Eileen H Bigio^{70

71}, Eloy Rodríguez-Rodríguez⁷², Jon Infante⁷², Carmen Lage⁷², Isabel González-Aramburu⁷², Pascual Sanchez-Juan⁷², Bernardino Ghetti⁵⁵, Julia Keith⁷³, Sandra E Black^{74

75

76

77

78}, Mario Masellis^{77

78

79

80}, Ekaterina Rogaeva⁸¹, Charles Duyckaerts^{82

83}, Alexis Brice⁸³, Suzanne Lesage⁸³, Georgia Xiromerisiou⁸⁴, Matthew J Barrett⁸⁵, Bension S Tilley⁸⁶, Steve Gentleman⁸⁶, Giancarlo Logroscino^{87

88}, Geidy E Serrano⁸⁹, Thomas G Beach⁸⁹, Ian G McKeith⁹⁰, Alan J Thomas⁹⁰, Johannes Attems⁹⁰, Christopher M Morris⁹⁰, Laura Palmer⁹¹, Seth Love⁹², Claire Troakes⁹³, Safa Al-Sarraj⁹⁴, Angela K Hodges⁹³, Dag Aarsland^{93

95}, Gregory Klein⁹⁶, Scott M Kaiser⁹⁷, Randy Woltjer⁹⁸, Pau Pastor¹¹, Lynn M Bekris⁹⁹, James B Leverenz¹⁰⁰, Lilah M Besser¹⁰¹, Amanda Kuzma¹⁰², Alan E Renton¹⁰³, Alison Goate¹⁰⁴, David A Bennett⁹⁶, Clemens R Scherzer¹⁰⁵, Huw R Morris¹⁰⁶, Raffaele Ferrari⁴, Diego Albani¹⁰⁷, Stuart Pickering-Brown¹⁰⁸, Kelley Faber¹⁰⁹, Walter A Kukull¹¹⁰, Estrella Morenas-Rodriguez^{111

112

113}, Alberto Lleó^{112

113}, Juan Fortea^{112

113}, Daniel Alcolea^{112

113}, Jordi Clarimon^{112

113}, Mike A Nalls^{114

115

116}, Luigi Ferrucci¹¹⁷, Susan M Resnick¹¹⁸, Toshiko Tanaka¹¹⁷, Tatiana M Foroud¹⁰⁹, Neill R Graff-Radford¹¹⁹, Zbigniew K Wszolek¹¹⁹, Tanis Ferman¹²⁰, Bradley F Boeve¹²¹, John A Hardy^{4

12

122

123

124}, Eric J Topol¹²⁵, Ali Torkamani¹²⁵, Andrew B Singleton^{3

116}, Mina Ryten^{5

6}, Dennis W Dickson⁷, Adriano Chiò^{40

41

126}, Owen A Ross^{7

127}, J Raphael Gibbs¹⁰, Clifton L Dalgard^{128

129}, Bryan J Traynor^{1

12

64}, Sonja W Scholz^{130

131}

Collaborators

American Genome Center:
Anthony R Sotis, Gauthaman Sukumar, Camille Alba, Nathaniel Lott, Elisa McGrath Martinez, Meila Tuck, Jatinder Singh, Dagmar Bacikova, Xijun Zhang, Daniel N Hupalo, Adelani Adeleye, Matthew D Wilkerson, Harvey B Pollard

Affiliations

¹ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
² Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
³ Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
⁴ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁵ NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK.
⁶ Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, London, UK.
⁷ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
⁸ Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁹ Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA.
¹⁰ Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
¹¹ Memory and Movement Disorders Units, Department of Neurology, University Hospital Mutua de Terrassa, Barcelona, Spain.
¹² Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.
¹³ Cerevel Therapeutics, Boston, MA, USA.
¹⁴ Genetics and Pharmacogenomics, Merck & Co., Inc., West Point, PA, USA.
¹⁵ Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
¹⁶ Taub Institute for Alzheimer Disease and the Aging Brain, and Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
¹⁷ Taub Institute for Alzheimer Disease and the Aging Brain, G. H. Sergievsky Center and Department of Neurology, Columbia University, New York, NY, USA.
¹⁸ Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
¹⁹ Department of Clinical Neurosciences, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, UK.
²⁰ Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
²¹ Clinical Memory Research Unit, Institution of Clinical Sciences Malmo, Lund University, Lund, Sweden.
²² Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
²³ Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
²⁴ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
²⁵ Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA.
²⁶ Neurology Service, University of Coimbra Hospital, Coimbra, Portugal.
²⁷ Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
²⁸ Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
²⁹ Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.
³⁰ Translational Immunology, Research Programs Unit, University of Helsinki, Helsinki, Finland.
³¹ Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
³² Department of Pathology, Medicum, University of Helsinki, Helsinki, Finland.
³³ HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland.
³⁴ Department of Clinical Medicine, Faculty of Health, UiT The Arctic University of Norway, Tromsø, Norway.
³⁵ Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
³⁶ Neuroscience Research Australia, Sydney, New South Wales, Australia.
³⁷ School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
³⁸ Brain and Mind Centre, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
³⁹ Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴⁰ Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy.
⁴¹ Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
⁴² Istituti Clinici Scientifici Maugeri, IRCCS, Milan, Italy.
⁴³ Department of Neurology, University Hospital of Cagliari, Cagliari, Italy.
⁴⁴ Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA.
⁴⁵ Dublin Brain Bank, Neuropathology Department, Beaumont Hospital, Dublin, Ireland.
⁴⁶ Montreal Neurological Institute and Hospital, Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada.
⁴⁷ Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
⁴⁸ Transversal Translational Medicine, Luxembourg Institute of Health, Strassen, Luxembourg.
⁴⁹ Parkinson Research Clinic, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg.
⁵⁰ Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
⁵¹ Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA.
⁵² Department of Neurology, New York University School of Medicine, New York, NY, USA.
⁵³ Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁵⁴ Michigan Brain Bank, University of Michigan Medical School, Ann Arbor, MI, USA.
⁵⁵ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵⁶ Department of Neurodegenerative Diseases, Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen and German Center for Neurodegenerative Diseases, Tübingen, Germany.
⁵⁷ Fondazione Policlinico Universitario Agostino Gemelli IRCCS Università Cattolica del Sacro Cuore, Rome, Italy.
⁵⁸ Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
⁵⁹ Bio4Dreams-Business Nursery for Life, Milan, Italy.
⁶⁰ Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
⁶¹ Department of Neuropathology, School of Medicine, University of California Irvine, Irvine, CA, USA.
⁶² Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA.
⁶³ Department of Pathology & Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA.
⁶⁴ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
⁶⁵ Neuroregeneration and Stem Cell Programs, Institute of Cell Engineering, Johns Hopkins University Medical Center, Baltimore, MD, USA.
⁶⁶ Department of Pharmacology and Molecular Science, Johns Hopkins University Medical Center, Baltimore, MD, USA.
⁶⁷ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University Medical Center, Baltimore, MD, USA.
⁶⁸ Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA.
⁶⁹ Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
⁷⁰ Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁷¹ Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁷² Neurology Service, University Hospital Marqués de Valdecilla-IDIVAL-UC-CIBERNED, Santander, Spain.
⁷³ Department of Anatomical Pathology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
⁷⁴ Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁷⁵ Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁷⁶ Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
⁷⁷ Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
⁷⁸ LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
⁷⁹ Cognitive & Movement Disorders Clinic, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
⁸⁰ Department of Medicine, Division of Neurology, University of Toronto, Toronto, Ontario, Canada.
⁸¹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
⁸² Department of Neuropathology Escourolle, Paris Brain Institute, Sorbonne Universités, Paris, France.
⁸³ Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, AP-HP, Hôpital Pitié-Salpêtrière, DMU Neuroscience 6, Paris, France.
⁸⁴ Department of Neurology, University Hospital of Larissa, University of Thessalia, Larissa, Greece.
⁸⁵ Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA.
⁸⁶ Neuropathology Unit, Department of Brain Sciences, Imperial College London, London, UK.
⁸⁷ Department of Basic Medicine Neurosciences and Sense Organs, University Aldo Moro, Bari, Italy.
⁸⁸ Center for Neurodegenerative Diseases and the Aging Brain - Department of Clinical Research in Neurology of the University of Bari at 'Pia Fondazione Card G. Panico' Hospital Tricase (Le), Bari, Italy.
⁸⁹ Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
⁹⁰ Newcastle Brain Tissue Resource, Translational and Clinical Research Institute, Biomedical Research Building, Newcastle University, Newcastle upon Tyne, UK.
⁹¹ South West Dementia Brain Bank, Bristol Medical School, University of Bristol, Bristol, UK.
⁹² Dementia Research Group, Bristol Medical School, University of Bristol, Bristol, UK.
⁹³ Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁹⁴ Department of Clinical Neuropathology and London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College Hospital and King's College London, London, UK.
⁹⁵ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
⁹⁶ Rush Alzheimer's Disease Center, Rush University, Chicago, IL, USA.
⁹⁷ Department of Neuropathology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁹⁸ Department of Neurology, Oregon Health & Sciences University, Portland, OR, USA.
⁹⁹ Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
¹⁰⁰ Cleveland Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
¹⁰¹ Institute for Human Health and Disease Intervention, Florida Atlantic University, Boca Raton, FL, USA.
¹⁰² Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰³ Ronald M. Loeb Center for Alzheimer's Disease, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰⁴ Ronald M. Loeb Center for Alzheimer's Disease, Nash Family Department of Neuroscience, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰⁵ Precision Neurology Program, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰⁶ Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, University College London, London, UK.
¹⁰⁷ Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
¹⁰⁸ Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
¹⁰⁹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
¹¹⁰ National Alzheimer's Coordinating Center, Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹¹¹ Biomedizinisches Centrum, Biochemie, Ludwig-Maximilians-Universität München & Deutsches Zentrum für Neurodegenerative Erkrankungen, Munich, Germany.
¹¹² Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
¹¹³ The Network Center for Biomedical Research in Neurodegenerative Diseases, Madrid, Spain.
¹¹⁴ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
¹¹⁵ Data Tecnica International, Glen Echo, MD, USA.
¹¹⁶ Center for Alzheimer's and Related Dementias, National Institute on Aging, Bethesda, MD, USA.
¹¹⁷ Longitudinal Studies Section, National Institute on Aging, Baltimore, MD, USA.
¹¹⁸ Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA.
¹¹⁹ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
¹²⁰ Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA.
¹²¹ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
¹²² UK Dementia Research Institute of UCL, UCL Institute of Neurology, University College London, London, UK.
¹²³ UCL Movement Disorders Centre, University College London, London, UK.
¹²⁴ Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
¹²⁵ Scripps Research Translational Institute, Scripps Research, La Jolla, CA, USA.
¹²⁶ Institute of Cognitive Sciences and Technologies, C.N.R., Rome, Italy.
¹²⁷ Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA.
¹²⁸ Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
¹²⁹ The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
¹³⁰ Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA. sonja.scholz@nih.gov.
¹³¹ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA. sonja.scholz@nih.gov.

^# Contributed equally.

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 disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Publication types

Multicenter Study
Research Support, N.I.H., Intramural

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Alzheimer Disease / genetics
Case-Control Studies
Gene Expression Profiling
Genetic Predisposition to Disease
Genome, Human
Genome-Wide Association Study*
Glucosylceramidase / genetics
Humans
Lewy Body Disease / genetics*
Nuclear Proteins / genetics
Parkinson Disease / genetics
Polymorphism, Single Nucleotide
Tumor Suppressor Proteins / genetics
alpha-Synuclein / genetics

Substances

Adaptor Proteins, Signal Transducing
BIN1 protein, human
Nuclear Proteins
SNCA protein, human
Tumor Suppressor Proteins
alpha-Synuclein
GBA protein, human
Glucosylceramidase

Abstract

Publication types

MeSH terms

Substances

Grants and funding