Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts.

Adult Aged Aged, 80 and over Antigens, CD / genetics Biomarkers Cognitive Dysfunction / etiology Cohort Studies Cross-Sectional Studies Disease Progression Female Genome-Wide Association Study Glucosylceramidase / genetics Humans Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics Longitudinal Studies Male Middle Aged Organic Cation Transport Proteins / genetics Parkinson Disease / genetics Phenotype Risk Assessment
Apolipoprotein E GBA Parkinson's disease genomewide association study

Journal

Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688

Informations de publication

Date de publication:
12 2019
Historique:
received: 09 05 2019
revised: 17 07 2019
accepted: 24 07 2019
pubmed: 11 9 2019
medline: 23 6 2020
entrez: 11 9 2019
Statut: ppublish

Résumé

Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson's disease, however, has not been well studied. To test the association between genetic variants and the clinical features of Parkinson's disease on a genomewide scale. We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease-risk variants, were also investigated post hoc for candidate associations with these phenotypes. Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58-2.62]; P value = 3.46E-8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for α-2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52-0.75]; P value = 4.74E-8). In the targeted analysis, we found 9 associations between known Parkinson's risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K; rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients. We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

Sections du résumé

BACKGROUND
Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson's disease, however, has not been well studied.
OBJECTIVES
To test the association between genetic variants and the clinical features of Parkinson's disease on a genomewide scale.
METHODS
We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease-risk variants, were also investigated post hoc for candidate associations with these phenotypes.
RESULTS
Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58-2.62]; P value = 3.46E-8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for α-2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52-0.75]; P value = 4.74E-8). In the targeted analysis, we found 9 associations between known Parkinson's risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K; rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients.
CONCLUSIONS
We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

Identifiants

DOI: 10.1002/mds.27845 PMID: 31505070 PMC: PMC7017876
pubmed: 31505070
doi: 10.1002/mds.27845
pmc: PMC7017876
mid: NIHMS1551389
doi:

Substances chimiques

Antigens, CD 0
Biomarkers 0
Organic Cation Transport Proteins 0
SLC44A1 protein, human 0
LRRK2 protein, human EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 EC 2.7.11.1
GBA protein, human EC 3.2.1.45
Glucosylceramidase EC 3.2.1.45

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

1839-1850

Subventions

Organisme : NCRR NIH HHS
ID : M01 RR000645
Pays : United States
Organisme : NCRR NIH HHS
ID : M01 RR000034
Pays : United States
Organisme : NCRR NIH HHS
ID : M01 RR000334
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS050095
Pays : United States
Organisme : NINDS NIH HHS
ID : P50 NS053488
Pays : United States
Organisme : NIA NIH HHS
ID : P50 AG005134
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 AG000949
Pays : United States
Organisme : NIA NIH HHS
ID : U19 AG062418
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS115144
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS100603
Pays : United States
Organisme : NIA NIH HHS
ID : Z01-AG000949-02
Pays : United States
Organisme : NCRR NIH HHS
ID : M01 RR000040
Pays : United States
Organisme : NCRR NIH HHS
ID : M01 RR000036
Pays : United States
Organisme : NINDS NIH HHS
ID : U24 NS095871
Pays : United States
Organisme : NCRR NIH HHS
ID : M01 RR000044
Pays : United States
Organisme : NCRR NIH HHS
ID : M01 RR000059
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS024778
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS082157
Pays : United States
Organisme : NCRR NIH HHS
ID : M01 RR001066
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NCRR NIH HHS
ID : M01 RR000042
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS095736
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS043128
Pays : United States
Organisme : NCRR NIH HHS
ID : M01 RR000827
Pays : United States
Organisme : NCRR NIH HHS
ID : M01 RR000847
Pays : United States

Informations de copyright

© 2019 International Parkinson and Movement Disorder Society.

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Auteurs

Hirotaka Iwaki (H)

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
Data Tecnica International, Glen Echo, Maryland, USA.

Cornelis Blauwendraat (C)

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

Hampton L Leonard (HL)

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
Data Tecnica International, Glen Echo, Maryland, USA.

Jonggeol J Kim (JJ)

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

Ganqiang Liu (G)

School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
Advanced Center for Parkinson's Disease Research, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Precision Neurology Program, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Jodi Maple-Grødem (J)

The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.
Department of Chemistry, Bioscience and Environmental Engineering, University in Stavanger, Stavanger, Norway.

Jean-Christophe Corvol (JC)

Assistance-Publique Hôpitaux de Paris, ICM, INSERM UMRS 1127, CNRS 7225, ICM, Department of Neurology and CIC Neurosciences, Pitié-Salpêtrière Hospital, Paris, France.

Lasse Pihlstrøm (L)

Department of Neurology, Oslo University Hospital, Oslo, Norway.

Marlies van Nimwegen (M)

Radboud University Medical Centre, Donders Institute for Brain, Cognition, and Behaviour; Department of Neurology, Nijmegen, The Netherlands.

Samantha J Hutten (SJ)

The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA.

Khanh-Dung H Nguyen (KH)

Translational Genome Sciences, Biogen, Cambridge, Massachusetts, USA.

Jacqueline Rick (J)

Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Shirley Eberly (S)

Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, USA.

Faraz Faghri (F)

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
Department of Computer Science, University of Illinois Urbana-Champaign, Champaign, Illinois, USA.

Peggy Auinger (P)

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

Kirsten M Scott (KM)

Department of Clinical Neurosciences, University of Cambridge, John van Geest Centre for Brain Repair, Cambridge, United Kingdom.

Ruwani Wijeyekoon (R)

Department of Clinical Neurosciences, University of Cambridge, John van Geest Centre for Brain Repair, Cambridge, United Kingdom.

Vivianna M Van Deerlin (VM)

Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Parelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Dena G Hernandez (DG)

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

J Raphael Gibbs (JR)

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

Kumaraswamy Naidu Chitrala (KN)

Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.

Aaron G Day-Williams (AG)

Flagship Labs 60 Inc, Cambridge, Massachusetts, USA.
Statistical Genetics, Biogen, Cambridge, Massachusetts, USA.

Alexis Brice (A)

Institut du cerveau et de la moelle épinière ICM, Paris, France.
Sorbonne Université SU, Paris, France.
INSERM UMR1127, Paris, France.

Guido Alves (G)

The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.
Department of Chemistry, Bioscience and Environmental Engineering, University in Stavanger, Stavanger, Norway.
Department of Neurology, Stavanger University Hospital, Stavanger, Norway.

Alastair J Noyce (AJ)

Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom.
Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, London, United Kingdom.

Ole-Bjørn Tysnes (OB)

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

Jonathan R Evans (JR)

Department of Neurology, Nottingham University NHS Trust, Nottingham, United Kingdom.

David P Breen (DP)

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland.
Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, Scotland.
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.

Karol Estrada (K)

Translational Genome Sciences, Biogen, Cambridge, Massachusetts, USA.

Claire E Wegel (CE)

Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, USA.

Fabrice Danjou (F)

Institut du cerveau et de la moelle épinière ICM, Paris, France.

David K Simon (DK)

Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Harvard Medical School, Boston, Massachusetts, USA.

Ole Andreassen (O)

NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Norway.
Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway, Norway.

Bernard Ravina (B)

Voyager Therapeutics, Cambridge, Massachusetts, USA.
Department of Neurology, University of Rochester School of Medicine, Rochester, New York, USA.

Mathias Toft (M)

Department of Neurology, Oslo University Hospital, Oslo, Norway.
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Peter Heutink (P)

German Center for Neurodegenerative Diseases-Tubingen, Tuebingen, Germany.
HIH Tuebingen, Tubingen, Tuebingen, Germany.

Bastiaan R Bloem (BR)

Radboud University Medical Centre, Donders Institute for Brain, Cognition, and Behaviour; Department of Neurology, Nijmegen, The Netherlands.

Daniel Weintraub (D)

Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Veterans Affairs, Philadelphia, Pennsylvania, USA.

Roger A Barker (RA)

Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.

Caroline H Williams-Gray (CH)

Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.

Bart P van de Warrenburg (BP)

Radboud University Medical Centre, Donders Institute for Brain, Cognition, and Behaviour; Department of Neurology, Nijmegen, The Netherlands.

Jacobus J Van Hilten (JJ)

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

Clemens R Scherzer (CR)

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

Andrew B Singleton (AB)

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

Mike A Nalls (MA)

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
Data Tecnica International, Glen Echo, Maryland, USA.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Genomewide association study of Parkinson's...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Genomewide association study of Parkinson's...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Sujet âgé de 80 ans ou plus › Genomewide association study of Parkinson's...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Antigènes de différenciation › Antigènes CD › Genomewide association study of Parkinson's...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Genomewide association study of Parkinson's...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Troubles de la cognition › Dysfonctionnement cognitif › Genomewide association study of Parkinson's...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Genomewide association study of Parkinson's...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études transversales › Genomewide association study of Parkinson's...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Évolution de la maladie › Genomewide association study of Parkinson's...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Genomewide association study of Parkinson's...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Glycosidases › Glucosidases › Glucosylceramidase › Genomewide association study of Parkinson's...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genomewide association study of Parkinson's...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines associées à la maladie de Parkinson › Leucine-rich repeat serine-threonine protein kinase-2 › Genomewide association study of Parkinson's...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études longitudinales › Genomewide association study of Parkinson's...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Genomewide association study of Parkinson's...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Protéines transporteurs de solutés › Transporteurs de cations organiques › Genomewide association study of Parkinson's...
questionsmedicales.fr › Maladies du système nerveux › Maladies neurodégénératives › Maladie de Parkinson › Genomewide association study of Parkinson's...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Genomewide association study of Parkinson's...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Appréciation des risques › Genomewide association study of Parkinson's...