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Neurology Genetics
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August 2019; 5 (4) ArticleOpen Access

Genetic risk of Parkinson disease and progression:

An analysis of 13 longitudinal cohorts

Hirotaka Iwaki, Cornelis Blauwendraat, View ORCID ProfileHampton L. Leonard, Ganqiang Liu, View ORCID ProfileJodi Maple-Grødem, Jean-Christophe Corvol, View ORCID ProfileLasse Pihlstrøm, Marlies van Nimwegen, Samantha J. Hutten, Khanh-Dung H. Nguyen, Jacqueline Rick, Shirley Eberly, View ORCID ProfileFaraz Faghri, Peggy Auinger, Kirsten M. Scott, Ruwani Wijeyekoon, Vivianna M. Van Deerlin, Dena G. Hernandez, Aaron G. Day-Williams, Alexis Brice, View ORCID ProfileGuido Alves, Alastair J. Noyce, Ole-Bjørn Tysnes, Jonathan R. Evans, David P. Breen, Karol Estrada, Claire E. Wegel, View ORCID ProfileFabrice Danjou, David K. Simon, Bernard Ravina, Mathias Toft, Peter Heutink, Bastiaan R. Bloem, Daniel Weintraub, Roger A. Barker, Caroline H. Williams-Gray, Bart P. van de Warrenburg, Jacobus J. Van Hilten, Clemens R. Scherzer, Andrew B. Singleton, Mike A. Nalls
First published July 9, 2019, DOI: https://doi.org/10.1212/NXG.0000000000000348
Hirotaka Iwaki
From the Laboratory of Neurogenetics (H.I., C.B., H.L.L., F.F., D.G.H., A.B.S., M.A.N.), National Institute on Aging, National Institutes of Health, Bethesda; Data Tecnica International (H.I., M.A.N.), Glen Echo, MD; Precision Neurology Program (G.L., C.R.S.), Harvard Medical School, Brigham and Women's Hospital; Neurogenomics Laboratory (G.L., C.R.S.), Harvard Medical School, Brigham and Women's Hospital; Ann Romney Center for Neurologic Diseases (G.L., C.R.S.), Brigham and Women's Hospital, Boston, MA; The Norwegian Centre for Movement Disorders (J.M.-G., G.A.), Stavanger University Hospital; Department of Chemistry (J.M.-G., G.A.), Bioscience and Environmental Engineering, University of Stavanger, Norway; Assistance-Publique Hôpitaux de Paris (J.-C.C.), ICM, INSERM UMRS 1127, CNRS 7225, ICM, Department of Neurology and CIC Neurosciences, Pitié-Salpêtrière Hospital, Paris, France; Department of Neurology (L.P., M.T.), Oslo University Hospital, Norway; Department of Neurology (M.N., B.R.B., B.P.W.), Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands; Michael J Fox Foundation (S.J.H.), New York; Translational Genome Sciences (K.-D.H.N, K.E.), Biogen, Cambridge, MA; Department of Neurology University of Pennsylvania (J.R.), Philadelphia, PA; Department of Biostatistics and Computational Biology (S.E.), University of Rochester, NY; Department of Computer Science (F.F.), University of Illinois Urbana-Champaign; Department of Neurology (P.A.), Center for Health + Technology, University of Rochester, NY; Department of Clinical Neurosciences (K.M.S., R.W.), University of Cambridge, John van Geest Centre for Brain Repair, UK; Department of Pathology and Laboratory Medicine (V.M.V.D.), Center for Neurodegenerative Disease Research, Parelman School of Medicine at the University of Pennsylvania, Philadelphia; Genetics and Pharmacogenomics (A.G.D.-W.), Merck Research Laboratory, Boston, MA; Statistical Genetics (A.G.D.-W.), Biogen, Cambridge, MA; Institut du cerveau et de la moelle épinière ICM (A.B., F.D.); Sorbonne Université SU (A.B.); INSERM UMR1127 (A.B.), Paris, France; Department of Neurology (G.A.), Stavanger University Hospital, Norway; Preventive Neurology Unit (A.J.N.), Wolfson Institute of Preventive Medicine, Queen Mary University of London; Department of Molecular Neuroscience (A.J.N.), UCL Institute of Neurology, London, UK; Department of Neurology (O.-B.T.), Haukeland University Hospital; University of Bergen (O.-B.T.), Bergen, Norway; Department of Neurology (J.R.E.), Nottingham University NHS Trust, UK; Centre for Clinical Brain Sciences (D.P.B.), University of Edinburgh; Anne Rowling Regenerative Neurology Clinic (D.P.B.), University of Edinburgh; Usher Institute of Population Health Sciences and Informatics (D.P.B.), University of Edinburgh, Scotland; Department of Medical and Molecular Genetics (C.E.W.), Indiana University, Indianapolis; Department of Neurology (D.K.S.), Beth Israel Deaconess Medical Center; Harvard Medical School (D.K.S.), Boston; Voyager Therapeutics (B.R.), Cambridge, MA; Department of Neurology (B.R.), University of Rochester School of Medicine, NY; Institute of Clinical Medicine (M.T.), University of Oslo, Norway; German Center for Neurodegenerative Diseases-Tubingen (P.H.); HIH Tuebingen (P.H.), Germany; Department of Psychiatry (D.W.), University of Pennsylvania School of Medicine; Department of Veterans Affairs (D.W.), Philadelphia, PA; and Department of Clinical Neurosciences (R.A.B., C.H.W.-G.), University of Cambridge, UK; Department of Neurology (J.J.V.H.), Leiden University Medical Center, The Netherlands.
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Cornelis Blauwendraat
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Hampton L. Leonard
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Ganqiang Liu
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Jodi Maple-Grødem
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Jean-Christophe Corvol
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Lasse Pihlstrøm
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Marlies van Nimwegen
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Samantha J. Hutten
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Khanh-Dung H. Nguyen
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Jacqueline Rick
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Shirley Eberly
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Faraz Faghri
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Peggy Auinger
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Kirsten M. Scott
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Ruwani Wijeyekoon
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Vivianna M. Van Deerlin
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Dena G. Hernandez
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Aaron G. Day-Williams
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Alexis Brice
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Guido Alves
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Alastair J. Noyce
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Ole-Bjørn Tysnes
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Jonathan R. Evans
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David P. Breen
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Karol Estrada
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Claire E. Wegel
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Fabrice Danjou
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David K. Simon
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Bernard Ravina
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Mathias Toft
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Peter Heutink
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Bastiaan R. Bloem
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Daniel Weintraub
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Roger A. Barker
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Caroline H. Williams-Gray
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Bart P. van de Warrenburg
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Jacobus J. Van Hilten
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Clemens R. Scherzer
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Andrew B. Singleton
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Mike A. Nalls
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Full PDF
Citation
Genetic risk of Parkinson disease and progression:
An analysis of 13 longitudinal cohorts
Hirotaka Iwaki, Cornelis Blauwendraat, Hampton L. Leonard, Ganqiang Liu, Jodi Maple-Grødem, Jean-Christophe Corvol, Lasse Pihlstrøm, Marlies van Nimwegen, Samantha J. Hutten, Khanh-Dung H. Nguyen, Jacqueline Rick, Shirley Eberly, Faraz Faghri, Peggy Auinger, Kirsten M. Scott, Ruwani Wijeyekoon, Vivianna M. Van Deerlin, Dena G. Hernandez, Aaron G. Day-Williams, Alexis Brice, Guido Alves, Alastair J. Noyce, Ole-Bjørn Tysnes, Jonathan R. Evans, David P. Breen, Karol Estrada, Claire E. Wegel, Fabrice Danjou, David K. Simon, Bernard Ravina, Mathias Toft, Peter Heutink, Bastiaan R. Bloem, Daniel Weintraub, Roger A. Barker, Caroline H. Williams-Gray, Bart P. van de Warrenburg, Jacobus J. Van Hilten, Clemens R. Scherzer, Andrew B. Singleton, Mike A. Nalls
Neurol Genet Aug 2019, 5 (4) e348; DOI: 10.1212/NXG.0000000000000348

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This article has a correction. Please see:

  • Errata - August 01, 2019
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    Figure 1 Forest plots for GBA (p.N370S and p.T408M) variants and symptoms of Parkinson disease

    DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism; DIGPD = Drug Interaction with Genes in Parkinson's Disease; HBS = Harvard Biomarkers Study; NET-PD_LS1 = NIH Exploratory Trials in Parkinson's Disease Large Simple Study 1; Oslo = Oslo PD study; ParkFit = ParkFit study; ParkWest = the Norwegian ParkWest study; PDBP = Parkinson's Disease Biomarker Program; PICNICS = Parkinsonism: Incidence and Cognitive and Non-motor heterogeneity In CambridgeShire; PPMI = Parkinson's Progression Markers Initiative; PreCEPT/PostCEPT = Parkinson Research Examination of CEP-1347 Trial with a subsequent prospective study; ProPark = Profiling Parkinson's Disease study; Udall = Morris K. Udall Centers for Parkinson's Research. * Indicates Beta in a Cox model; ** indicates Beta in a logistic model at baseline.

  • Figure 2
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    Figure 2 Forest plots for GBA (p.E365K) variants and symptoms of Parkinson disease

    DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism; DIGPD = Drug Interaction with Genes in Parkinson's Disease; HBS = Harvard Biomarkers Study; NET-PD_LS1 = NIH Exploratory Trials in Parkinson's Disease Large Simple Study 1; Oslo = Oslo PD study; ParkFit = ParkFit study; ParkWest = the Norwegian ParkWest study; PDBP = Parkinson's Disease Biomarker Program; PICNICS = Parkinsonism: Incidence and Cognitive and Non-motor heterogeneity In CambridgeShire; PPMI = Parkinson's Progression Markers Initiative; PreCEPT/PostCEPT = Parkinson Research Examination of CEP-1347 Trial with a subsequent prospective study; ProPark = Profiling Parkinson's Disease study; Udall = Morris K. Udall Centers for Parkinson's Research. * Indicates Beta in a Cox model; ** indicates Beta in a logistic model at baseline; *** indicates Beta in a linear mixed model.

  • Figure 3
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    Figure 3 Forest plots for non-GBA risk variants/genetic risk score and symptoms or features of Parkinson disease

    DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism; DIGPD = Drug Interaction with Genes in Parkinson's Disease; HBS = Harvard Biomarkers Study; NET-PD_LS1 = NIH Exploratory Trials in Parkinson's Disease Large Simple Study 1; Oslo = oslo PD study; ParkFit = ParkFit study; ParkWest = the Norwegian ParkWest study; PDBP = Parkinson's Disease Biomarker Program; PICNICS = Parkinsonism: Incidence and Cognitive and Non-motor heterogeneity In CambridgeShire; PPMI = Parkinson's Progression Markers Initiative; PreCEPT/PostCEPT = Parkinson Research Examination of CEP-1347 Trial with a subsequent prospective study; ProPark = Profiling Parkinson's Disease study; Udall = Morris K. Udall Centers for Parkinson's Research. * Indicates Beta in a Cox model; ** indicates Beta in a logistic model at baseline; *** indicates Beta in a linear mixed model.

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An analysis of 13 longitudinal cohorts

  1. Hirotaka Iwaki, MD,
  2. Cornelis Blauwendraat, PhD,
  3. Hampton L. Leonard, MS,
  4. Ganqiang Liu, PhD,
  5. Jodi Maple-Grødem, PhD,
  6. Jean-Christophe Corvol, MD, PhD,
  7. Lasse Pihlstrøm, MD, PhD,
  8. Marlies van Nimwegen, PhD,
  9. Samantha J. Hutten, PhD,
  10. Khanh-Dung H. Nguyen, PhD,
  11. Jacqueline Rick, PhD,
  12. Shirley Eberly, MS,
  13. Faraz Faghri, MS,
  14. Peggy Auinger, MS,
  15. Kirsten M. Scott, MRCP, MPhil,
  16. Ruwani Wijeyekoon, MRCP,
  17. Vivianna M. Van Deerlin, MD, PhD,
  18. Dena G. Hernandez, PhD,
  19. Aaron G. Day-Williams, PhD,
  20. Alexis Brice, MD,
  21. Guido Alves, MD, PhD,
  22. Alastair J. Noyce, MRCP, PhD,
  23. Ole-Bjørn Tysnes, MD, PhD,
  24. Jonathan R. Evans, MRCP, PhD,
  25. David P. Breen, MRCP, PhD,
  26. Karol Estrada, PhD,
  27. Claire E. Wegel, MPH,
  28. Fabrice Danjou, MD, PhD,
  29. David K. Simon, MD, PhD,
  30. Bernard Ravina, MD,
  31. Mathias Toft, MD, PhD,
  32. Peter Heutink, PhD,
  33. Bastiaan R. Bloem, MD, PhD,
  34. Daniel Weintraub, MD,
  35. Roger A. Barker, MRCP, PhD,
  36. Caroline H. Williams-Gray, MRCP, PhD,
  37. Bart P. van de Warrenburg, MD, PhD,
  38. Jacobus J. Van Hilten, MD, PhD,
  39. Clemens R. Scherzer, MD,
  40. Andrew B. Singleton, PhD and
  41. Mike A. Nalls, PhD
  1. From the Laboratory of Neurogenetics (H.I., C.B., H.L.L., F.F., D.G.H., A.B.S., M.A.N.), National Institute on Aging, National Institutes of Health, Bethesda; Data Tecnica International (H.I., M.A.N.), Glen Echo, MD; Precision Neurology Program (G.L., C.R.S.), Harvard Medical School, Brigham and Women's Hospital; Neurogenomics Laboratory (G.L., C.R.S.), Harvard Medical School, Brigham and Women's Hospital; Ann Romney Center for Neurologic Diseases (G.L., C.R.S.), Brigham and Women's Hospital, Boston, MA; The Norwegian Centre for Movement Disorders (J.M.-G., G.A.), Stavanger University Hospital; Department of Chemistry (J.M.-G., G.A.), Bioscience and Environmental Engineering, University of Stavanger, Norway; Assistance-Publique Hôpitaux de Paris (J.-C.C.), ICM, INSERM UMRS 1127, CNRS 7225, ICM, Department of Neurology and CIC Neurosciences, Pitié-Salpêtrière Hospital, Paris, France; Department of Neurology (L.P., M.T.), Oslo University Hospital, Norway; Department of Neurology (M.N., B.R.B., B.P.W.), Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands; Michael J Fox Foundation (S.J.H.), New York; Translational Genome Sciences (K.-D.H.N, K.E.), Biogen, Cambridge, MA; Department of Neurology University of Pennsylvania (J.R.), Philadelphia, PA; Department of Biostatistics and Computational Biology (S.E.), University of Rochester, NY; Department of Computer Science (F.F.), University of Illinois Urbana-Champaign; Department of Neurology (P.A.), Center for Health + Technology, University of Rochester, NY; Department of Clinical Neurosciences (K.M.S., R.W.), University of Cambridge, John van Geest Centre for Brain Repair, UK; Department of Pathology and Laboratory Medicine (V.M.V.D.), Center for Neurodegenerative Disease Research, Parelman School of Medicine at the University of Pennsylvania, Philadelphia; Genetics and Pharmacogenomics (A.G.D.-W.), Merck Research Laboratory, Boston, MA; Statistical Genetics (A.G.D.-W.), Biogen, Cambridge, MA; Institut du cerveau et de la moelle épinière ICM (A.B., F.D.); Sorbonne Université SU (A.B.); INSERM UMR1127 (A.B.), Paris, France; Department of Neurology (G.A.), Stavanger University Hospital, Norway; Preventive Neurology Unit (A.J.N.), Wolfson Institute of Preventive Medicine, Queen Mary University of London; Department of Molecular Neuroscience (A.J.N.), UCL Institute of Neurology, London, UK; Department of Neurology (O.-B.T.), Haukeland University Hospital; University of Bergen (O.-B.T.), Bergen, Norway; Department of Neurology (J.R.E.), Nottingham University NHS Trust, UK; Centre for Clinical Brain Sciences (D.P.B.), University of Edinburgh; Anne Rowling Regenerative Neurology Clinic (D.P.B.), University of Edinburgh; Usher Institute of Population Health Sciences and Informatics (D.P.B.), University of Edinburgh, Scotland; Department of Medical and Molecular Genetics (C.E.W.), Indiana University, Indianapolis; Department of Neurology (D.K.S.), Beth Israel Deaconess Medical Center; Harvard Medical School (D.K.S.), Boston; Voyager Therapeutics (B.R.), Cambridge, MA; Department of Neurology (B.R.), University of Rochester School of Medicine, NY; Institute of Clinical Medicine (M.T.), University of Oslo, Norway; German Center for Neurodegenerative Diseases-Tubingen (P.H.); HIH Tuebingen (P.H.), Germany; Department of Psychiatry (D.W.), University of Pennsylvania School of Medicine; Department of Veterans Affairs (D.W.), Philadelphia, PA; and Department of Clinical Neurosciences (R.A.B., C.H.W.-G.), University of Cambridge, UK; Department of Neurology (J.J.V.H.), Leiden University Medical Center, The Netherlands.
  1. Correspondence
    Dr. Nalls nallsm{at}mail.nih.gov
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Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. Norwegian Parkinson's Association (Norges Parkinsonforbund) The Norwegian association for public health (Nasjonalforeningen for folkehelsen)

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. Advisory board for Pfizer, Theranexus, Zambon, and BMS

Gifts:
  1. NONE

Funding for travel or speaker honoraria:
  1. Speaker honoraria from Zambon, travel grant from Zambon and Abbvie

Editorial Boards:
  1. Movement Disorders journal, associate editor, 2015

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. Research grant from Actelion

Research Support, Government Entities:
  1. Grants from the French Ministry of Health, ANR

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. Grant from the Michael J Fox Foundation, France Parkinson Stock/Stock Options, Medical Equipment & Materials: Stock option in B&A Therapeutics

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. (1) Southeastern Norway Regional Health Authority, project leader, PhD-grant, 2017-current

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. Biogen, Scientist, 3 years (2015-2018, where my involvement with this work is linked to)

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. 1) Commercial entity: Voyager Pharmaceuticals 2) Commercial entity: TevaPharmaceuticals 3) Commercial entity: Vaccinex

Research Support, Government Entities:
  1. 1) NIH 5 U01 NS080840-05 Holloway 04/01/14 ? 03/31/19 Data Coordination Center for STEADY-PD3. Data analysis. 2) NIH 5 U01 NS089666-03 Oakes 09/01/15 ? 06/30/20 Phase 3 Trial of Inosine for Parkinson?s Disease - DCC. Data analysis.

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. Michael J Fox Foundation

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. (1) National Institute on Aging, National Institutes of Health

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. (1) Mayo Clinic

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. (1) Wellcome Trust Clinical PhD Fellowship 106565/Z/14/Z

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. Member, Editorial Board,

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. Merck

Research Support, Government Entities:
  1. NIH AG010124 NIH AG017586 NIH AG032953 NIH R01-NS94003 NIH R21-AG046499 NIH SBIR R44NS089423

Research Support, Academic Entities:
  1. Penn Center for Precision Medicine

Research Support, Foundations and Societies:
  1. ALS Association

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. Government employee NIH Biologist

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. Biogen, Associate Director, 2/15-11/16 Merck, Director, 12/16 - 7/18 Flagship Labs 60 Inc., Vice President, 8/18-Present

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. (1) FWO (Research Foundation Flanders) (2) ERC (European Research Council) (3) BMBF (Bundesministeriums f?r Bildung and Forschung-Berlin Germany)

Gifts:
  1. NONE

Funding for travel or speaker honoraria:
  1. Conference honorarium Tokyo, Sumitomo Dainippon Pharma Consulting honorarium, Sanofi, France

Editorial Boards:
  1. (1)Neurology and Clinical Neuroscience, Editorial Board Member, 2012-(2)Parkinsonism and Related Disorders,Editorial Board Member,2008-(3)Brain,Editorial Board Member,2007-(4)Neurodegenerative Diseases, Editorial Board Member, 2003-(5) The Cerebellum, Editorial Board Member, 2001-(6) Neurogenetics, Editorial Board Member, 2001-

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. Grants from French Research Agency, EU

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. (1)France Parkinson Association, (2) Roger de Spoelberch Foundation (ref. R12123DD), (3)ARN (Agence nationale pour la Recherche)

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. (1)Norwegian Parkinson's disease Association

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. Britannia Pharmaceuticals

Gifts:
  1. NONE

Funding for travel or speaker honoraria:
  1. Profile Pharmaceuticals

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. Parkinson's UK Virginia Kieley Benefaction

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. Given lectures for several pharmaceutical companies

Editorial Boards:
  1. Acta Neurologica Scandinavica. More than 10 years

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. 1) UCB Pharma 2)Global Kinetics Limited 3)Britannia Pharmaceuticals 4)AbbVie pharmaceuticals

Gifts:
  1. NONE

Funding for travel or speaker honoraria:
  1. (1) UCB pharma: speaker honoraria, (2) Britannia pharmaceuticals: travel and conference fees (3) AbbVie pharamceuticals: honoraria, travel and conference fees (4) Ipsen Pharmaceuticals: travel and conference fees

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. (1) Glaxo-Smithkline

Speakers' Bureaus:
  1. 1) UCB pharma 2)Britannia Pharmaceuticals 3)AbbVie pharamceuticals 4)Global Kinetics

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. (1) Wellcome Clinical Research Career Development Fellowship, (2) Edmond J. Safra Foundation via the Michael J. Fox Foundation, (3) Rowling Scholarship from the Anne Rowling Regenerative Neurology Clinic, University of Edinburgh

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. Former employee of Biogen (3 years) Current employee of Biomarin (6 months)

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. Michael J Fox Foundation for Parkinson's Disease Research, The Foundation for Peripheral Neuropathy

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. (1) Scientific Advisory Board for the Weston Brain Institute (non-profit) (2) Linked Clinical Trials Committee; Cure Parkinson's Trust (non-profit) (3) Steering Committee for phase 2 clinical trial of Nilotinib in Parkinson's disease; The Michael J Fox Foundation (non-profit) (4) Steering Committee for the

Gifts:
  1. NONE

Funding for travel or speaker honoraria:
  1. (1) Parkinson Study Group Executive Committee member (non-profit); travel expenses paid for attending the annual meeting. (2) Steering Committee for the

Editorial Boards:
  1. NONE

Patents:
  1. NONE

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  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. (1) Lysosomal Therapeutics, Inc (commercial); consultant for clinical product development (2) Cerevance, Inc. (commercial); Consultant for clinical trial

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. (1) Research grant to fund clinical research study from Lysosomal Therapeutics (2) Research grant to fund clinical study from BioElectron Technologies (3) Laboratory research grant (Mission Therapeutics; Commercial)

Research Support, Government Entities:
  1. (1) National Institutes of Health (NINDS); 1R01NS086352; PI; 2014 - 2019 (2) National Institutes of Health (NINDS); 1R21NS094840; PI; 2017 - 2019 (3) National Institutes of Health (NINDS); 1P50NS094733; Outreach Coordinator; 2015 - 2020 (4) National Institutes of Health (NINDS); subcontract from Massachusetts General Hospital; site PI (SURE-PD3 clinical trial); 2016 - 2019

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. (1) Weston Brain Institute Advisor Fellowship (2) National Parkinson Foundation Community Grant Award for wellness programs

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

Scientific Advisory Boards:
  1. Commercial: Voyager Therapeutics Non Profit: Michael J Fox Foundation

Gifts:
  1. NONE

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  1. NONE

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  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. Voyager Therapeutics and Praxis Precision Medicine

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NIH, DOD, Michael J Fox Foundation

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. Michael J Fox Foundation

Stock/Stock Options/Board of Directors Compensation:
  1. Commercial - Voyager Therapeutics and Praxis Precision Medicine

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

Funding for travel or speaker honoraria:
  1. Speaker honoraria from Roche.

Editorial Boards:
  1. Editorial board member of PLOS One, Frontiers Neurology, Case Reports in Neurological Medicine

Patents:
  1. NONE

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  1. NONE

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  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. Research grants from the Research Council of Norway, Regional Health Authority South-Eastern Norway

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. Research grants from the Michael J. Fox Foundation, Norwegian Parkinson Research Fund

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

Patents:
  1. NONE

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  1. NONE

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  1. NONE

Consultancies:
  1. Commercial entity Neuron23 LLC

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

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  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. (1) Michael J Fox Foundation (non-profit entity); (2) Parkinson Vereniging (non-profit entity); (3) Movement Disorder Society (non-profit entity); (4) Brian Grant Foundation (non-profit entity);

Gifts:
  1. NONE

Funding for travel or speaker honoraria:
  1. (1) AbbVie (speaker's fee) (commercial entity); (2) Zambon (speaker's fee) (commercial entity); (3) Bial (speaker's fee) (commercial entity); (4) Kyowa Kirin (speaker's fee) (commercial entity)

Editorial Boards:
  1. (1) Movement Disorders, member editorial board (2006-2010) (no compensation); (2) Physiotherapy Canada,member editorial board (2007- 2016) (no compensation); (3) Tijdschrift voor Neurologie & Neurochirurgie, editor- in-chief (until 2013) (no compensation); (4) Journal of Parkinson's Disease, associate editor (2010- present) (no compensation).

Patents:
  1. NONE

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  1. NONE

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  1. NONE

Consultancies:
  1. Zambon (commercial entity)

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. (1) UCB (commercial entity); (2) AbbVie (commercial entity); (3) Verily (commercial entity).

Research Support, Government Entities:
  1. (1) Grant of the Parkinson Society Canada?s National Research Program. Role: co-investigator. 2014 (2) Grant of Euregio (European Fund Regional Development). Role: project leader. 2014 (3) Proeftuin Zorg van de Toekomst. Grant of European Fund Regional Development (EFRO). Role: project leader. 2016. (5) Privacy en security in personalized care. Grant of Dutch province of Gelderland. Role: co-investigator. 2016

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. (1) Netherlands Organization for Scientific Research (non-profit entity); (2) Michael J Fox Foundation (non-profit entity); (3) Parkinson Vereniging (non-profit entity); (4) Prinses Beatrix Foundation(non-profit entity); (5) Stichting Parkinson Fonds (non-profit entity); (6) National Parkinson Foundation (non-profit entity); (7) Hersenstichting (non-profit entity)

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

Scientific Advisory Boards:
  1. Commercial - honoraria for consultancy from Acadia, Alkahest, CHDI Foundation, Clintrex LLC, F. Hoffmann-La Roche Ltd and Sunovion Non-profit - CHDI, ADCS, ATRI

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. Associate Editor for Movement Disorders Journal

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other activities:
  1. Licensing fees from the University of Pennsylvania for the QUIP and QUIP-RS

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NINDS, P50 NS053488, Investigator, 2007-2018 NIA, U19 AG10483-22, DSMB Chair, 2013-

Research Support, Academic Entities:
  1. U. of Pennsylvania internal grant funding

Research Support, Foundations and Societies:
  1. Michael J. Fox Foundation for Parkinson's Research, PI,

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License fee payments, Technology or Inventions:
  1. Licensing fees from the University of Pennsylvania for licensing of Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease.

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. Expert testimony for defense in 2012-2017 in three lawsuits related to impulse control disorders or antipsychotic use in Parkinson's disease

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. Co-Editor in Chief, Journal of Neurology. Editorial Boaard of Journal of Parkinson's Disease. .

Patents:
  1. NONE

Publishing Royalties:
  1. Neuroscience at a glance. 5th Edition. 2012.Wiley.

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. Sana; BlueRock; Nova Nordisk; FCDI; Cellino;LCT

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. I have recieved funding from the EU; Parkinson's UK; CHDI; Cure PD; Rosetrees trust; Michael J Fox Foundation; Wellcome Trust; MRC.

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

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  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. Movement Disorders, Editorial Board Member, 2015 to present.

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. (1) RCUK/UKRI Medical Research Council, grant reference MR/R007446/1, Clinician Scientist Fellowship holder, 2018- 2023. (2) NIHR Biomedical Research Centre Award to the University of Cambridge/Cambridge University Hospitals NHS Trust, 2017-2022.

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. (1) Patrick Berthoud Trust (2) Raymond and Beverly Sackler Foundation (3) The Rosetrees Trust (4) Academy of Medical Sciences, UK (5) Stevenage Biosciences Catalyst (6) Addenbrooke's Charitable Trust (7) The Evelyn Trust (8) Parkinson's UK, grant reference G1507 (9) The Michael J Fox Foundation, grant reference 14912

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for travel or speaker honoraria:
  1. Travel stipends from the Parkinson and Movement Disorder Society and European Academy of Neurology for lectures at their international meetings, non-profit

Editorial Boards:
  1. 1. Review Editor for Frontiers in Neurology (section Movement Disorders), 2011 - present 2. Member editorial board of Cerebellum & Ataxias, 2014 - present 3. Review editor for Tijdschrift voor Neurologie en Neurochirurgie, 2013-2016 All without compensation.

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. (1) Bioblast Pharma

Research Support, Government Entities:
  1. ZonMW, 9003037604 and 733051066, funding agency, 2016 - present

Research Support, Academic Entities:
  1. (1) Radboud University Medical Center, Nijmegen, the Netherlands

Research Support, Foundations and Societies:
  1. Hersenstichting Gossweiler Foundation

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. Partial funding Travel/congres expences by ABBVIE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NONE

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. International Parkinson Disease Foundation Van Alkemade - Keuls Foundation AbbVie

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. Sanofi Scientific Advisory Committee for MOVES-PD Phase 2 Clinical Trial of Venglustat in GBA-PD

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. 2008 - present Editorial Board Member, Biomarkers in Medicine 2011 - present Editorial Board Member, Neurogenetics

Patents:
  1. Held by Brigham & Women's Hospital: United States Letters Patent for Identification of dysregulated genes in patients with neurologic diseases, Express Mail No.: EV448719517; Date of Deposit: November 3, 2005 Held by Brigham & Women's Hospital and Sanofi Genzyme on biomarkers for proteinopathies, pending

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. AMGEN

Speakers' Bureaus:
  1. NONE

Other activities:
  1. C.R.S. has previously had scientific collaborations with Pfizer, Opko, Proteome Sciences.

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NIH/NINDS U01NS100603 (Scherzer, Role: PI) 09/30/16-08/31/21 NIH/NIA RF1AG057331 (Role: Multi-PI: Scherzer, Feany, Fraenkel) 09/15/17-06/30/22 NIH/NINDS U01NS095736 (Scherzer, Role: PI) 09/30/16-08/31/19 NIH/NINDS U01 NS082157 (Scherzer, Role: PI) 09/30/12-07/31/18

Research Support, Academic Entities:
  1. Harvard NeuroDiscovery Center

Research Support, Foundations and Societies:
  1. American Parkinson Disease Association (Role: Center Director) 09/01/18-08/31/28 Michael J. Fox Foundation (Scherzer, Role: PI) 03/24/17- 03/23/19 M.E.M.O. Hoffman Foundation

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for travel or speaker honoraria:
  1. (1) 23andMe, travel payment

Editorial Boards:
  1. Serve on: Annals of Neurology Lancet Neurology Neurogenetics Neurobiology of Disease Neurodegenerative Diseases Brain Journal of Parkinson's Disease

Patents:
  1. Patent pending for panel of markers to diagnose stroke

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NIH Intramural funding Department of Defense, W81XWH-09-2-0128, PI, 2009-2011

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
  1. NONE

Scientific Advisory Boards:
  1. NONE

Gifts:
  1. NONE

Funding for Travel or Speaker Honoraria:
  1. NONE

Editorial Boards:
  1. NONE

Patents:
  1. NONE

Publishing Royalties:
  1. NONE

Employment, Commercial Entity:
  1. NONE

Consultancies:
  1. NONE

Speakers' Bureaus:
  1. NONE

Other Activities:
  1. NONE

Clinical Procedures or Imaging Studies:
  1. NONE

Research Support, Commercial Entities:
  1. NONE

Research Support, Government Entities:
  1. NIH employee (2005-current)

Research Support, Academic Entities:
  1. NONE

Research Support, Foundations and Societies:
  1. NONE

Stock/Stock Options/Board of Directors Compensation:
  1. NONE

License Fee Payments, Technology or Inventions:
  1. NONE

Royalty Payments, Technology or Inventions:
  1. NONE

Stock/Stock Options, Research Sponsor:
  1. NONE

Stock/Stock Options, Medical Equipment & Materials:
  1. NONE

Legal Proceedings:
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Abstract

Objective To determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression.

Methods We evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed.

Results We confirmed the importance of GBA on phenotypes. GBA variants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69–6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04–20.60]). We also replicated previously reported associations of GBA variants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16–1.52] for the C allele of rs76904798) and an intronic variant in PMVK and the development of wearing-off effects (HR 1.66 [1.19–2.31] for the C allele of rs114138760). Age at onset was associated with TMEM175 variant p.M393T (−0.72 [−1.21 to −0.23] in years), the C allele of rs199347 (intronic region of GPNMB, 0.70 [0.27–1.14]), and G allele of rs1106180 (intronic region of CCDC62, 0.62 [0.21–1.03]).

Conclusions This study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.

Glossary

ESS=
Epworth Sleepiness Scale;
FDR=
false discovery rate;
GRS=
genetic risk score;
GWAS=
genome-wide association study;
HR=
hazard ratio;
HY=
Hoehn and Yahr scale;
MAF=
minor allele frequency;
MDS=
Movement Disorder Society;
MMSE=
Mini-Mental State Examination;
MoCA=
Montreal Cognitive Assessment;
MSQ=
Mayo Sleep Questionnaire;
NMS=
nonmotor symptom;
OR=
odds ratio;
PC=
principal component;
PDSS=
Parkinson's Disease Sleep Scale;
PPMI=
Parkinson's Progression Markers Initiative;
RBD=
rapid eye movement sleep behavior disorder;
RBDSQ=
RBD Screening Questionnaire;
RLS=
restless legs syndrome;
SEADL=
Schwab and England Activities of Daily Living Scale;
UPDRS=
Unified Parkinson's Disease Rating Scale

Parkinson disease is one of the most common neurodegenerative diseases, with an estimated lifetime risk as high as 1%–2%.1 Parkinson disease is traditionally characterized by motor features such as bradykinesia, rigidity, and tremor. However, in addition to these motor symptoms, patients with Parkinson disease also develop nonmotor symptoms (NMSs), which include depression, cognitive decline, sleep abnormalities, reduced olfaction, and autonomic dysfunction.2 Collectively, the combined spectrum of motor and NMSs more accurately reflects the multisystem nature of the disease. Patients with Parkinson disease may present with various combinations of symptoms and show differences in the rates of progression.3 The application of modern molecular genetic approaches over the last decade has revealed a significant number of genetic risk loci for idiopathic Parkinson disease.4,–,7 However, in comparison with case-control genome-wide association study (GWAS), analyzing how genetic factors influence clinical presentation and progression requires longitudinal cohorts with much more detailed observations. Such data are sparse, and individual cohorts are often small in size and quite varied, posing a challenge both in sample size and heterogeneity.

In an attempt to address these issues, we collected data from 13 distinct longitudinal Parkinson disease cohorts with detailed clinical data, including assessment of disease progression. We sought to determine whether Parkinson disease genetic risk factors, either in the form of known GWAS variants or an aggregate genetic risk score (GRS), are associated with changes in clinical progression and the disease features.

Methods

Study design and participants

A total of 13 Parkinson disease cohorts from North America, Europe, and Australia participated in the study. Nine were prospective observational cohorts and the rest were from randomized clinical trials. The observational cohorts were Drug Interaction with Genes in Parkinson's Disease (DIGPD), Harvard Biomarkers Study (HBS), Oslo Parkinson's Disease study (partly including retrospective data), The Norwegian ParkWest study (ParkWest), Parkinson's Disease Biomarker Program (PDBP), Parkinsonism: Incidence and Cognitive and Non-motor heterogeneity In CambridgeShire (PICNICS), Parkinson's Progression Markers Initiative (PPMI), Profiling Parkinson's disease study (ProPark), and the Morris K. Udall Centers for Parkinson's Research (Udall). The 4 cohorts from randomized clinical trials were Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP), NIH Exploratory Trials in Parkinson's Disease Large Simple Study 1, ParkFit study (ParkFit), and Parkinson Research Examination of CEP-1347 Trial with a subsequent prospective study (PreCEPT/PostCEPT). Information on these cohorts can be found in appendix e-1 (links.lww.com/NXG/A169). Subsets of participants from the cohorts who provided DNA and were nonrelated participants with PD, diagnosed at age 18 years or later, and of European ancestry were included in the study. Participants' information and genetic samples were obtained under appropriate written consent and with local institutional and ethical approvals.

Genotyping SNPs and calculation of GRS

Oslo samples were genotyped on the Illumina Infinium OmniExpress array, DIGPD samples were genotyped by Illumina Multi-Ethnic Genotyping Array, and all other samples were genotyped on the NeuroX array.8 The quality control process of variant calling included GenTrain score <0.7, minor allele frequency (MAF) >0.05 (for sample quality control but not in our analysis of rare risk factors), and Hardy-Weinberg equilibrium test statistic >10−6. Sample-specific quality control included a sample call rate of >0.95, confirmation of sex through genotyping, homozygosity quantified by F within ± 3 SD from the population mean, European ancestry confirmed by principal-components analysis with 1000 Genomes data as the reference, and genetic relatedness of any 2 individuals <0.125. Detailed information regarding NeuroX and the quality control process has been described previously.9 In the present study, we investigated 31 single nucleotide polymorphisms (SNPs) previously shown to be significantly associated with Parkinson disease.10,–,12 In addition, we also calculated a GRS for each participant based on these variants. The scores were transformed into Z-scores within each cohort and treated as an exposure, with effect estimates based on 1 SD change from the population mean. The list of 31 SNPs and the GRS calculation method are provided in table e-1 (links.lww.com/NXG/A170).

Furthermore, principal components (PCs) were created for each data set from genotypes using PLINK. For the PC calculation, variants were filtered for MAF (>0.05), genotype missingness (<0.05), and Hardy-Weinberg equilibrium (p ≥ 10−5). The remaining variants were pruned (using a 50-kb window, with a 5 SNP shift per window and r2 threshold of 0.5), and PCs were calculated using the pruned variants.

Measurements

The following clinical measurements and binomial outcomes were recorded longitudinally (table e-2 links.lww.com/NXG/A171): total and subscores of the Unified Parkinson's Disease Rating Scale (UPDRS) or the Movement Disorder Society revised UPDRS version (MDS-UPDRS); modified Hoehn and Yahr scales (HY); modified Schwab and England Activities of Daily Living Scale; and scores for the Mini-Mental State Examination (MMSE), The SCales for Outcomes in PArkinson's disease (SCOPA)-Cognition, and Montreal Cognitive Assessment (MoCA). Each was treated as a continuous outcome. For the UPDRS and MDS-UPDRS scores specifically, we took Z-scores of the total and subscores (except for part 4 at baseline) to compare the original and revised UPDRS versions. The conversion was applied to the scores for all subsequent visits. For UPDRS part 4, most participants had very low scores or 0 at baseline, so we normalized across all observations within each cohort. We also analyzed binomial outcomes. If we had access to the raw data, we used common cutoff values, which had been tested and reported specificity of 85% or more in patients' population. The binomial outcomes include existence of family history (1st-degree relative. 1st- and 2nd-degree relatives in HBS, PreCEPT, ProPark, and Udall), hyposmia (University of Pennsylvania Smell Identification Test < 21,13 or answering “yes” to question 2 in the NMS questionnaire), cognitive impairment (SCOPA-Cognition < 23, MMSE < 27, or MoCA < 24,14,15 or diagnosed with The Diagnostic and Statistical Manual of Mental Disorders -IV criteria for dementia), wearing off (UPDRS/MDS-UPDRS part 4 off time >0 or physician's diagnosis), dyskinesia (UPDRS/MDS-UPDRS part 4 dyskinesia time >0 or physician's diagnosis), depression (Beck Depression Inventory > 14 [PICNICS used 9 instead of 14], Hamilton Depression Rating Scale > 9, Geriatric Depression Scale [GRS] > 5,16 or physician's diagnosis), constipation (MDS-UPDRS part 1 item 11 > 0, or answering “yes” to question 5 in the NMS questionnaire), excessive daytime sleepiness (Epworth sleepiness scale > 9,17 insomnia [MDS-UPDRS part 1, item 7 > 0], rapid eye movement sleep behavior disorder [RBD]) (answered “yes” to question 1 on the Mayo Sleep Questionnaire [MSQ],18 or RBD screening questionnaire [RBDSQ >5],19 restless legs syndrome [RLS]) (answered “yes” to MSQ question 3,20 or RLS diagnosis positive by RBDSQ), and the progression to HY ≥ 3 (HY3, representing moderate to severe disease). The individual definitions of these binomial outcomes are summarized in table e-2 (links.lww.com/NXG/A171). Age, sex, years of education, age at motor symptom onset, and whether the patient was treated with levodopa or dopamine agonists at each visit were also recorded for adjustments.

Statistical analysis

Cohort-level analysis

We analyzed the association between exposures and outcomes using appropriate additive models. Covariates of interest were not available for all cohorts; therefore, the model specifications were slightly different between cohorts (detailed in table e-3, links.lww.com/NXG/A172). Briefly, the associations between an SNP/GRS and age at onset were analyzed by linear regression modeling adjusting for population stratification (PC1 and PC2). The association between family history of Parkinson disease and SNP/GRS was analyzed with a logistic regression model adjusting for PC1/2. For continuous variables, linear regression modeling adjusting for sex, education, PC1/2, age at onset, years from diagnosis, family history, and treatment status was applied. For those who had multiple observations, random intercept was added to adjust for repeated measurements of the same individual. For binomial outcomes, the logistic regression at baseline observation was applied using the same covariates as the continuous models. Those that were negative at baseline were further analyzed by a Cox regression with the same covariates but with treatment status as a time-varying covariate. Observations with missing variables were excluded from the analyses.

Meta-analysis

We applied inverse weighting (precision method) for each combination of outcome-predictor association and combined the estimates from the 13 different cohorts in a fixed effect model. Multiple test correction for SNPs was controlled with an overall false discovery rate (FDR) of 0.05 per outcome being considered significant. Similarly, multiple testing of outcomes for GRS was corrected with an FDR of 0.05, but across all traits. In addition, as a test of homogeneity, I2 indices and forest plots were used for quantitative assessment. As a sensitivity analysis, we conducted up to 13 iterations of the meta-analyses for the 12 cohorts excluding each cohort per iteration. This analysis provides information regarding heterogeneity of the cohorts and how one specific cohort exclusion affects the results. The range of estimates and maximum p values for the iterations were included. Finally, we conducted the 13-cohort meta-analysis in a random effects model with restricted maximum likelihood estimation using the same multiple testing correction.

All the above analyses were conducted with PLINK version 1.9, and R version 3.4.4 (64-bit). Statistical tests were all 2 sided.

Data availability

Qualified investigators can request raw data through the organizations' homepages (PDBP: pdbp.ninds.nih.gov/, PPMI: ppmi-info.org/) or collaboration.

Results

A total of 23,423 visits by 4,307 patients with a median follow-up period of 2.97 years (quartile range of [1.63–4.94] years) were eligible for the analysis. The baseline characteristics of the cohorts are shown in table 1. The mean ages at onset varied from 54 to 69 years; the average disease durations at cohort entry ranged from less than 1 to 10 years, and the mean observation periods were between 1.2 and 6.8 years. All DATATOP, ParkWest, PPMI, and PreCEPT participants were dopaminergic therapy naive at baseline; patients in the other cohorts were not. In the primary analysis of 13 cohorts, 17 associations were identified as significant after FDR correction (table 2, and more information in table e-4, links.lww.com/NXG/A173). Overwhelmingly, 10 were associated with GBA variants. In particular, GBA p.E365K (rs2230288) was associated with 2.37- (1.53–3.66) (95% CI) fold higher odds of having cognitive impairment at baseline (p = 1.09 × 10−4) and 2.78- (1.88–4.11) fold higher hazard ratio (HR) of developing cognitive impairment during follow-up among those who were negative for cognitive impairment at baseline (p = 2.97 × 10−7). This SNP was also associated with a higher mean on the HY at 0.10 (0.04–0.16) (p = 1.53 × 10−3), but the test of homogeneity was rejected (p = 0.017, I2 = 48.9%). In addition, it was associated with the development of an RBD among those who did not have the disorder at baseline. Other GBA mutations, p.N370S (rs767763715) and p.T408M (rs75548401), were both associated with a higher HR of reaching HY3 (4.59 [2.60–8.10] for p.N370S [p = 1.58 × 10−7] and 1.93 [1.34–2.78] for p.T408M [p = 4.40 × 10−4]). GBA p.N370N was also associated with a higher risk of developing wearing-off, dyskinesia, and daytime sleepiness. p.T408M was associated with a 6.48 (2.04–20.60) times higher odds ratio (OR) of having an RBD symptom at baseline (p = 1.53 × 10−3).

View this table:
Table 1

Summary characteristics of 13 cohorts

View this table:
Table 2

Meta-analysis for 13 cohorts and the results of sensitivity analysis

Two LRRK2 variants in our 31 SNPs of interest were significantly associated with outcomes. LRRK2 p.G2019S (rs34637584) was associated with higher odds of having a family history of Parkinson disease (OR 3.54 [1.72–7.29], p = 6.06 × 10−4), and the T allele of rs76904798 (intergenic at the 5′ end of LRRK2) was associated with a higher HR of reaching HY3 (HR 1.33 [1.16–1.52] for the T allele, p = 5.27 × 10−5).

Age at onset was inversely associated with the Z value of the GRS (−0.60 [−0.89 to −0.31] years per +1 SD, p = 5.33 × 10−5). Moreover, it was associated with rs34311866 (TMEM175 p.M393T), the C allele of rs199347 (intronic region of GPNMB), and the G allele of rs1106180 (intronic region of CCDC62).

The majority (14/17) of associations showed good accord across cohorts (I2 < 50%), and the forest plots (figures 1–3) also illustrate this qualitatively. Furthermore, up to 13 iterations of the leave-one-out analysis assessed 15 associations of which outcomes were measured in more than 2 cohorts and showed a small range of betas. The maximum p value of 13 iterations was less than 0.05 for all associations except for rs114138769 (intron of PMVK) and rs76763715 (GBA p.N370S) for wearing-off. A meta-analysis with a random effect model also detected 9 associations after the same FDR correction, although the model is more conservative than a fixed model.

Figure 1
Figure 1 Forest plots for GBA (p.N370S and p.T408M) variants and symptoms of Parkinson disease

DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism; DIGPD = Drug Interaction with Genes in Parkinson's Disease; HBS = Harvard Biomarkers Study; NET-PD_LS1 = NIH Exploratory Trials in Parkinson's Disease Large Simple Study 1; Oslo = Oslo PD study; ParkFit = ParkFit study; ParkWest = the Norwegian ParkWest study; PDBP = Parkinson's Disease Biomarker Program; PICNICS = Parkinsonism: Incidence and Cognitive and Non-motor heterogeneity In CambridgeShire; PPMI = Parkinson's Progression Markers Initiative; PreCEPT/PostCEPT = Parkinson Research Examination of CEP-1347 Trial with a subsequent prospective study; ProPark = Profiling Parkinson's Disease study; Udall = Morris K. Udall Centers for Parkinson's Research. * Indicates Beta in a Cox model; ** indicates Beta in a logistic model at baseline.

Figure 2
Figure 2 Forest plots for GBA (p.E365K) variants and symptoms of Parkinson disease

DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism; DIGPD = Drug Interaction with Genes in Parkinson's Disease; HBS = Harvard Biomarkers Study; NET-PD_LS1 = NIH Exploratory Trials in Parkinson's Disease Large Simple Study 1; Oslo = Oslo PD study; ParkFit = ParkFit study; ParkWest = the Norwegian ParkWest study; PDBP = Parkinson's Disease Biomarker Program; PICNICS = Parkinsonism: Incidence and Cognitive and Non-motor heterogeneity In CambridgeShire; PPMI = Parkinson's Progression Markers Initiative; PreCEPT/PostCEPT = Parkinson Research Examination of CEP-1347 Trial with a subsequent prospective study; ProPark = Profiling Parkinson's Disease study; Udall = Morris K. Udall Centers for Parkinson's Research. * Indicates Beta in a Cox model; ** indicates Beta in a logistic model at baseline; *** indicates Beta in a linear mixed model.

Figure 3
Figure 3 Forest plots for non-GBA risk variants/genetic risk score and symptoms or features of Parkinson disease

DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism; DIGPD = Drug Interaction with Genes in Parkinson's Disease; HBS = Harvard Biomarkers Study; NET-PD_LS1 = NIH Exploratory Trials in Parkinson's Disease Large Simple Study 1; Oslo = oslo PD study; ParkFit = ParkFit study; ParkWest = the Norwegian ParkWest study; PDBP = Parkinson's Disease Biomarker Program; PICNICS = Parkinsonism: Incidence and Cognitive and Non-motor heterogeneity In CambridgeShire; PPMI = Parkinson's Progression Markers Initiative; PreCEPT/PostCEPT = Parkinson Research Examination of CEP-1347 Trial with a subsequent prospective study; ProPark = Profiling Parkinson's Disease study; Udall = Morris K. Udall Centers for Parkinson's Research. * Indicates Beta in a Cox model; ** indicates Beta in a logistic model at baseline; *** indicates Beta in a linear mixed model.

Discussion

We conducted a meta-analysis with 13 longitudinal patient cohorts and identified multiple associations between genotypes and clinical phenotypic characteristics, including progression rates. Among these, GBA coding variants showed clear associations with the rate of cognitive decline (binomial outcome or UPDRS part 1 score) and motor symptom progression (HY, HY3), consistent with previous studies.12,21,–,25

In addition, we found associations between GBA variants and RBD and daytime sleepiness. A previous cross-sectional study with 120 Ashkenazi-Jewish patients reported a higher frequency of RBDSQ-detected RBD symptoms in GBA variant carriers.26 Our finding suggests that GBA is associated not only with baseline clinical presentation but also with disease progression.

An association between GBA and daytime sleepiness has been rarely documented. One study reported an association between sleep problems (as assessed by the Parkinson's Disease Sleep Scale) and GBA.27 However, this scale is a combined measure of daytime sleepiness and other aspects of sleep problems.

Finally, a GBA variant (p.N370S) was also associated with treatment-related complications of wearing-off and dyskinesia. Two studies have reported the association of GBA variants with these complications, with 1 positive and 1 negative result.28,29 The negative result may be due to insufficient power with only 19 patients with GBA mutations.

Overall, our study provides a distinct clinical profile of patients with GBA variants compared with those without. We note that with 63 carriers for p.N370S, 166 for p.T408M, and 217 for p.E365K, we have a reasonable power, but the number is yet not enough. And this may affect the results in seemingly different magnitudes of associations and the association for different traits per variants (e.g., motor complications with p.N370S and cognitive impairment with p.E365K). Another possible explanation is that although the effects are associated with the same gene, the biological activity or molecular mechanism could be different. Such an example has already been reported for LRRK2 p.G2019S and p.G2385R.30

Aside from GBA variants, the associations between close intergenic (5′_end) variant of LRRK2, rs76904798, and the faster development of motor symptom, and the intronic region variant of PMVK, rs114138760, and the development of wearing-off, were significant. This variant is 4.3 kb upstream from the 5′ end of LRRK2 and reported to be associated with LRRK2 gene expression changes in recent blood cis-expression quantitative trait loci (eQTL) study from the eQTLGen Consortium.31 In contrast, we did not find an association between rs34637584, LRRK2 coding mutation (p.G2019S) and motor progression. The p.G2019 variant is a rare variant (MAF 0.5% in our study), and our sample size was not adequate barring an extremely large effect size. The intronic region variant of PMVK, rs114138760, and the development of wearing-off was another finding. The biological effect of PMVK on PD has not been reported, but the variant is also located at close proximity of the GBA-SYT11 locus, so it is possible that its association was through a similar mechanism as GBA. Including the results of cross-sectional analysis, the associations of age at onset with rs34311866 (TMEM175, p.M393T), rs199347 (intron of GPNMB), and rs11060180 (intron of CCDC62) were found. TMEM175 has been reported to impair lysosomal and mitochondrial function and increase α-synuclein aggregation,32 although no functional data for this missense variant were studied. Of interest, the variant has recently been reported in another study as being associated with the age at onset.33 rs199347 is an eQTL increasing the brain expression of GPNMB,34 suggesting a causal link. Regarding rs1160180, no functional data are available in this locus.

We also evaluated the association between genetic risk variants and clinical outcomes by 2-step meta-analysis. This analysis is exploratory, and we acknowledge that this is biased toward the null due to power issues when partitioning studies randomly. However, we believe that it is helpful to assess the rigorousness of the associations we found in the primary analysis and to explore potential missed associations.

A strength of the current study was its design, incorporating multiple distinct independent Parkinson disease cohorts with longitudinal follow-ups. Although the cohorts contained patients at different disease stages, and some of the definition of outcomes were not identical, we analyzed each cohort separately and combined the results. Thus, the significant findings are consistent and applicable to the wider Parkinson disease populations. The forest plots showed that most of the estimates agree with each other despite the relative differences in the cohort characteristics. Another strength is the size of the study. The total number of genotyped and phenotyped patients with Parkinson disease (N = 4,307) is one of the largest to date for an investigation of disease progression.

The limitations of our study were as follows. First, we only included patients of European ancestry. It is uncertain whether the associations in the current study are also applicable to people from different ethnic backgrounds and further research is needed. Second, the current analysis could not distinguish causality, only basic associations. Different approaches, such as molecular-level assessment and Mendelian randomization, are crucial. Third, interaction effects between genes and other factors are another important research target not addressed in this report because of power constraints. For example, gene-by-smoking interactions for Parkinson disease were indicated recently35 and highlight the importance of correctly modeling gene-environment interactions. Finally, compared with the typical GWAS analysis (which includes tens of thousands of cases), the number of participants was small, and the outcomes of interest were not as simple or easily defined as with case-control distinctions in GWAS. Acknowledging the limitations, the list of associations provided here is valuable as a foundation for further studies and as an example that illustrates the potential of efforts to define the genetic basis of variability in presentation and course. Accounting for this variability, even in part, has the potential to positively affect etiology-based clinical trials by reducing variability between placebo and treatment groups and by providing better predictions of expected individual progression.

Study funding

This study is supported by the Intramural Research Program, the National Institute on Aging (NIA, Z01-AG000949-02), Biogen Idec, and the Michael J Fox Foundation for Parkinson's Research. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The authors had full access to the data in the study and had final responsibility for the decision to submit for publication.

Disclosure

H. Iwaki—grants: Michael J Fox Foundation. J. Maple-Grødem—grants: Norwegian Parkinson's Disease Association. J.-C. Corvol—advisory boards: Biogen, Air Liquide, BrainEver, Theranexus, BMS, Zambon, Pfizer, Ipsen, and AbbVie; grants: MJFF, Actelion, and Ipsen. L. Pihlstrøm—grants: Norwegian Health Association, South-East Norway Regional Health Authority, Norwegian Parkinson Research Fund, and Michael J. Fox Foundation. K.-D.H. Nguyen—stock ownership in medically related fields: Biotech/Pharmaceutical Industry. K.M. Scott—grants: Wellcome Trust PhD Fellowship. V.M. Van Deerlin—grants: NIH NS-053488. A.G. Day-Williams—stock ownership in medically related fields: Biogen and Merck. A. Brice—advisory boards: FWO and ERC; grants: JPND, ANR, Eranet Neuron, and Association France Parkinson. A.J. Noyce—honoraria: Britannia Pharmaceuticals; grants: Parkinson's UK (G-1606). J.R. Evans—advisory boards: AbbVie, Global Kinetics, and Allergan; honoraria: UCB, Allergan, and AbbVie. K. Estrada—stock ownership in medically related fields: Biogen. D.K. Simon—consultancies: Lysosomal Therapeutics, Inc.; advisory boards: Weston Brain Institute; honoraria: Parkinson Study Group, Harvard Medical School, Michael J Fox Foundation, and Biogen; grants: NIH, Weston Brain Institute, Mission Therapeutics, Inc., and BioElectron Technologies. B. Ravina—stock ownership in medically related fields: Voyager Therapeutics; consultancies: Michael J Fox Foundation. M. Toft—honoraria: Roche; grants: Research Council of Norway, South-Eastern Norway Regional Health Authority, and Michael J. Fox Foundation. B.R. Bloem—consultancies: AbbVie and Zambon; advisory boards: Michael J Fox Foundation; honoraria and speaker fees: AbbVie, Zambon, and Bial; grants: The Netherlands Organization for Scientific Research, the Michael J Fox Foundation, UCB, AbbVie, the Stichting Parkinson Fonds, the Hersenstichting Nederland, the Parkinson's Foundation, Verily Life Sciences, the Topsector Life Sciences and Health, and the Parkinson Vereniging. D. Weintraub—consultancies: Acadia, Alkahest, Anavex Life Sciences, BlackThorn Therapeutics, Bracket, Clintrex LLC, Sunovion, Theravance Biopharma, and the CHDI Foundation. R.A. Barker—consultancies: CDI and Oxford Biomedica; royalties: Springer and Wiley; grants: EU, NIHR, PUK, CPT, Rosetrees Trust, MRC, Wellcome Trust, and Evelyn Trust. C.H. Williams-Gray—grants: MRC Clinician Scientist fellowship, the NIHR Cambridge Biomedical Research Centre, the Michael J Fox Foundation, the Rosetrees Trust, the Evelyn Trust, and Addenbrookes Charitable Trust. B.P. van de Warrenburg—advisory boards: member of medical advisory boards and patient organizations; royalties: Reed Elsevier (for chapter in Dutch Neurology textbook); grants: Radboud University Medical Centre, ZonMW, Hersenstichting, and Bioblast Pharma. J.J. Van Hilten—grants: Alkemade-Keuls Foundation, Stichting Parkinson Fonds, Parkinson Vereniging, and The Netherlands Organisation for Health Research and Development. C.R. Scherzer—grants: NIH grants U01NS082157, U01NS095736, and U01NS100603. M.A. Nalls—consultancies: Lysosomal Therapies Inc., Vivid Genomics Inc., Kleiner Perkins Caufield & Byers, and Michael J. Fox Foundation. Go to Neurology.org/NG for full disclosures.

Acknowledgment

The authors thank all study participants and their family, investigators, and members of the following studies: Parkinson Study Group: Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP); Drug Interaction with Genes in Parkinson's Disease (DIGPD); Harvard Biomarkers Study (HBS); NET-PD_LS1, NIH Exploratory Trials in Parkinson's Disease Large Simple Study 1; Oslo PD study; ParkFit study; The Norwegian ParkWest study (ParkWest); Parkinson's Disease Biomarker Program (PDBP); Parkinsonism: Incidence and Cognitive and Non-motor heterogeneity In CambridgeShire (PICNICS); Parkinson's progression markers initiative (PPMI); Parkinson Study Group: Parkinson Research Examination of CEP-1347 Trial (PreCEPT) and its following study (PostCEPT); Profiling Parkinson's disease study (ProPark); and Morris K. Udall Centers for Parkinson's Research (Udall). They also thank the following grants and financial supporters of above studies; DATATOP was supported by a Public Health Service grant (NS24778) from the NINDS; by grants from the General Clinical Research Centers Program of the NIH at Columbia University (RR00645), the University of Virginia (RR00847), the University of Pennsylvania (RR00040), the University of Iowa (RR00059), Ohio State University (RR00034), Massachusetts General Hospital (RR01066), the University of Rochester (RR00044), Brown University (RR02038), Oregon Health Sciences University (RR00334), Baylor College of Medicine (RR00350), the University of California (RR00827), Johns Hopkins University (RR00035), the University of Michigan (RR00042), and Washington University (RR00036), the Parkinson's Disease Foundation at Columbia-Presbyterian Medical Center, the National Parkinson Foundation, the Parkinson Foundation of Canada, the United Parkinson Foundation, Chicago, the American Parkinson's Disease Association, New York, and the University of Rochester; DIGPD is supported by Assistance Publique Hôpitaux de Paris, funded by a grant from the French Ministry of Health (PHRC 2008, AOM08010) and a grant from the Agence Nationale pour la Sécurité des Médicaments (ANSM 2013); HBS is supported by the Harvard NeuroDiscovery Center, Michael J Fox Foundation, NINDS U01NS082157, U01NS100603, and the Massachusetts Alzheimer's Disease Research Center NIA P50AG005134; NET-PD_LS1 was supported by NINDS grants U01NS043128; OSLO is supported by the Research Council of Norway and South-Eastern Norway Regional Health Authority; ParkFit is supported by ZonMw (the Netherlands Organization for Health Research and Development [75020012]) and the Michael J Fox Foundation for Parkinson's research, VGZ (health insurance company), GlaxoSmithKline, and the National Parkinson Foundation; ParkWest is supported by the Research Council of Norway, the Western Norway Regional Health Authority, Stavanger University Hospital Research Funds, and the Norwegian Parkinson's Disease Association; PDBP is a consortium with NINDS initiative; PICNICS has received funding from the Cure Parkinson's Trust, the Van Geest Foundation and is supported by the NIH Research Cambridge Biomedical Research Centre; PPMI is supported by the Michael J Fox Foundation for Parkinson's research; PreCEPT and PostCEPT were funded by NINDS 5U01NS050095-05, Department of Defense Neurotoxin Exposure Treatment Parkinson's Research Program (Grant Number: W23RRYX7022N606), the Michael J Fox Foundation for Parkinson's Research, Parkinson's Disease Foundation, Lundbeck Pharmaceuticals. Cephalon Inc, Lundbeck Inc, John Blume Foundation, Smart Family Foundation, RJG Foundation, Kinetics Foundation, National Parkinson Foundation, Amarin Neuroscience LTD, CHDI Foundation Inc, NIH (NHGRI and NINDS), and Columbia Parkinson's Disease Research Center; ProPARK is funded by the Alkemade-Keuls Foundation, Stichting Parkinson Fonds, Parkinson Vereniging, and The Netherlands Organization for Health Research and Development; Udall is supported by the NINDS.

Appendix Authors

Table

Footnotes

  • Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.

  • The Article Processing Charge was funded by the NIH.

  • Received November 13, 2018.
  • Accepted in final form April 30, 2019.
  • Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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