Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease.

Apolipoprotein E4 / genetics Cognition Cognition Disorders / genetics Disease Progression Genetic Loci Genetic Predisposition to Disease Genome-Wide Association Study Glucosylceramidase / genetics Humans Longitudinal Studies Multifactorial Inheritance / genetics Mutation / genetics Parkinson Disease / genetics Proportional Hazards Models Risk Factors Survival Analysis Synapses / genetics

Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
06 2021
Historique:
received: 03 04 2019
accepted: 16 03 2021
pubmed: 8 5 2021
medline: 21 7 2021
entrez: 7 5 2021
Statut: ppublish

Résumé

A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10

Identifiants

DOI: 10.1038/s41588-021-00847-6 PMID: 33958783 PMC: PMC8459648
pubmed: 33958783
doi: 10.1038/s41588-021-00847-6
pii: 10.1038/s41588-021-00847-6
pmc: PMC8459648
mid: NIHMS1684407
doi:

Substances chimiques

Apolipoprotein E4 0
GBA protein, human EC 3.2.1.45
Glucosylceramidase EC 3.2.1.45

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

787-793

Subventions

Organisme : Medical Research Council
ID : MC_PC_17230
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R007446/1
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : U01 NS100603
Pays : United States
Organisme : NINDS NIH HHS
ID : U24 NS095871
Pays : United States
Organisme : NINDS NIH HHS
ID : K23 NS099380
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : U01 NS095736
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS115144
Pays : United States

Investigateurs

Jacobus J van Hilten (JJ)

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Auteurs

Ganqiang Liu (G)

Center for Advanced Parkinson Research, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
Precision Neurology Program of Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, China.
ORCID: 0000-0002-1921-9542

Jiajie Peng (J)

Center for Advanced Parkinson Research, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
Precision Neurology Program of Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
School of Computer Science, Northwestern Polytechnical University, Xi'an, Shaanxi, China.

Zhixiang Liao (Z)

Center for Advanced Parkinson Research, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
Precision Neurology Program of Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Joseph J Locascio (JJ)

Center for Advanced Parkinson Research, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
Precision Neurology Program of Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Jean-Christophe Corvol (JC)

Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Institut National de Santé et en Recherche Médicale, Centre National de Recherche Scientifique, Assistance Publique Hôpitaux de Paris, Département de Neurologie et de Génétique, Centre d'Investigation Clinique Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France.

Frank Zhu (F)

Center for Advanced Parkinson Research, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
Precision Neurology Program of Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Xianjun Dong (X)

Center for Advanced Parkinson Research, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
Precision Neurology Program of Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0002-8052-9320

Jodi Maple-Grødem (J)

The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.
Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway.
ORCID: 0000-0001-7142-0078

Meghan C Campbell (MC)

Departments of Neurology and Radiology, Washington University School of Medicine, St. Louis, MO, USA.

Alexis Elbaz (A)

Paris-Saclay University, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Inserm, Gustave Roussy, 'Exposome and heredity' team, Centre de researche en épidémiologie et santé des populations (CESP), Villejuif, France.
ORCID: 0000-0001-9724-5490

Suzanne Lesage (S)

Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Institut National de Santé et en Recherche Médicale, Centre National de Recherche Scientifique, Assistance Publique Hôpitaux de Paris, Département de Neurologie et de Génétique, Centre d'Investigation Clinique Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France.

Alexis Brice (A)

Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Institut National de Santé et en Recherche Médicale, Centre National de Recherche Scientifique, Assistance Publique Hôpitaux de Paris, Département de Neurologie et de Génétique, Centre d'Investigation Clinique Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France.

Graziella Mangone (G)

Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Institut National de Santé et en Recherche Médicale, Centre National de Recherche Scientifique, Assistance Publique Hôpitaux de Paris, Département de Neurologie et de Génétique, Centre d'Investigation Clinique Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France.

John H Growdon (JH)

Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Albert Y Hung (AY)

Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0003-3658-571X

Michael A Schwarzschild (MA)

Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Michael T Hayes (MT)

Center for Advanced Parkinson Research, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.

Anne-Marie Wills (AM)

Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Todd M Herrington (TM)

Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Bernard Ravina (B)

Praxis Precision Medicines, Cambridge, MA, USA.

Ira Shoulson (I)

Department of Neurology, Center for Health + Technology, University of Rochester, Rochester, NY, USA.

Pille Taba (P)

Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia.

Sulev Kõks (S)

Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Western Australia, Australia.
Perron Institute for Neurological and Translational Science, Perth, Western Australia, Australia.
ORCID: 0000-0001-6087-6643

Thomas G Beach (TG)

Banner Sun Health Research Institute, Sun City, AZ, USA.

Florence Cormier-Dequaire (F)

Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Institut National de Santé et en Recherche Médicale, Centre National de Recherche Scientifique, Assistance Publique Hôpitaux de Paris, Département de Neurologie et de Génétique, Centre d'Investigation Clinique Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France.

Guido Alves (G)

The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.
Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway.
Department of Neurology, Stavanger University Hospital, Stavanger, Norway.
ORCID: 0000-0003-0630-2870

Ole-Bjørn Tysnes (OB)

Department of Neurology, Haukeland University Hospital, Bergen, Norway.
Department of Clinical Medicine, University of Bergen, Bergen, Norway.

Joel S Perlmutter (JS)

Departments of Neurology and Radiology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA.
Program of Physical Therapy and Program of Occupational Therapy, Washington University School of Medicine, St. Louis, MO, USA.

Peter Heutink (P)

German Center for Neurodegenerative diseases (DZNE), Tübingen, Germany.
ORCID: 0000-0001-5218-1737

Sami S Amr (SS)

Translational Genomics Core of Partners HealthCare Personalized Medicine, Cambridge, MA, USA.

Jacobus J van Hilten (JJ)

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

Meike Kasten (M)

Institute of Neurogenetics, University of Lübeck, University Hospital of Schleswig-Holstein, Lübeck, Germany.
Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany.

Brit Mollenhauer (B)

Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
Paracelsus-Elena-Klinik, Kassel, Germany.

Claudia Trenkwalder (C)

Paracelsus-Elena-Klinik, Kassel, Germany.
Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany.

Christine Klein (C)

Institute of Neurogenetics, University of Lübeck, University Hospital of Schleswig-Holstein, Lübeck, Germany.

Roger A Barker (RA)

John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.

Caroline H Williams-Gray (CH)

John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Johan Marinus (J)

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

Clemens R Scherzer (CR)

Center for Advanced Parkinson Research, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. cscherzer@rics.bwh.harvard.edu.
Precision Neurology Program of Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. cscherzer@rics.bwh.harvard.edu.
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. cscherzer@rics.bwh.harvard.edu.
Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA. cscherzer@rics.bwh.harvard.edu.
ORCID: 0000-0002-0567-9193

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