Genetic risk of Parkinson disease and progression:: An analysis of 13 longitudinal cohorts

Hirotaka Iwaki¹, Cornelis Blauwendraat¹, Hampton L Leonard¹, Ganqiang Liu¹, Jodi Maple-Grødem¹, Jean-Christophe Corvol¹, Lasse Pihlstrøm¹, Marlies van Nimwegen¹, Samantha J Hutten¹, Khanh-Dung H Nguyen¹, Jacqueline Rick¹, Shirley Eberly¹, Faraz Faghri¹, Peggy Auinger¹, Kirsten M Scott¹, Ruwani Wijeyekoon¹, Vivianna M Van Deerlin¹, Dena G Hernandez¹, Aaron G Day-Williams¹, Alexis Brice¹, Guido Alves¹, Alastair J Noyce¹, Ole-Bjørn Tysnes¹, Jonathan R Evans¹, David P Breen¹, Karol Estrada¹, Claire E Wegel¹, Fabrice Danjou¹, David K Simon¹, Bernard Ravina¹, Mathias Toft¹, Peter Heutink¹, Bastiaan R Bloem¹, Daniel Weintraub¹, Roger A Barker¹, Caroline H Williams-Gray¹, Bart P van de Warrenburg¹, Jacobus J Van Hilten¹, Clemens R Scherzer¹, Andrew B Singleton¹, Mike A Nalls¹

Affiliations

Affiliation

¹ 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 UMR (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.

PMID: 31404238
PMCID: PMC6659137
DOI: 10.1212/NXG.0000000000000348

Genetic risk of Parkinson disease and progression:: An analysis of 13 longitudinal cohorts

Hirotaka Iwaki et al. Neurol Genet. 2019.

. 2019 Jul 9;5(4):e348.

doi: 10.1212/NXG.0000000000000348. eCollection 2019 Aug.

Authors

Affiliation

¹ 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 UMR (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.

PMID: 31404238
PMCID: PMC6659137
DOI: 10.1212/NXG.0000000000000348

Erratum in

Erratum: Genetic risk of Parkinson disease and progression: An analysis of 13 longitudinal cohorts.
[No authors listed] [No authors listed] Neurol Genet. 2019 Aug 15;5(4):e354. doi: 10.1212/NXG.0000000000000354. eCollection 2019 Aug. Neurol Genet. 2019. PMID: 31517058 Free PMC article.

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.

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Figures

**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. 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. 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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References

1. Elbaz A, Bower JH, Maraganore DM, et al. Risk tables for parkinsonism and Parkinson's disease. J Clin Epidemiol 2002;55:25–31. - PubMed
1. Chaudhuri KR, Healy DG, Schapira AHV; National Institute for Clinical Excellence. Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol 2006;5:235–245. - PubMed
1. Lewis SJG, Foltynie T, Blackwell AD, Robbins TW, Owen AM, Barker RA. Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005;76:343–348. - PMC - PubMed
1. Satake W, Nakabayashi Y, Mizuta I, et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet 2009;41:1303–1307. - PubMed
1. Simón-Sánchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 2009;41:1308–1312. - PMC - PubMed

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Genetic risk of Parkinson disease and progression:: An analysis of 13 longitudinal cohorts

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Genetic risk of Parkinson disease and progression:: An analysis of 13 longitudinal cohorts

Authors

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