Article Figures & Data
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.
Tables
An analysis of 13 longitudinal cohorts
- Hirotaka Iwaki, MD,
- Cornelis Blauwendraat, PhD,
- Hampton L. Leonard, MS,
- Ganqiang Liu, PhD,
- Jodi Maple-Grødem, PhD,
- Jean-Christophe Corvol, MD, PhD,
- Lasse Pihlstrøm, MD, PhD,
- Marlies van Nimwegen, PhD,
- Samantha J. Hutten, PhD,
- Khanh-Dung H. Nguyen, PhD,
- Jacqueline Rick, PhD,
- Shirley Eberly, MS,
- Faraz Faghri, MS,
- Peggy Auinger, MS,
- Kirsten M. Scott, MRCP, MPhil,
- Ruwani Wijeyekoon, MRCP,
- Vivianna M. Van Deerlin, MD, PhD,
- Dena G. Hernandez, PhD,
- Aaron G. Day-Williams, PhD,
- Alexis Brice, MD,
- Guido Alves, MD, PhD,
- Alastair J. Noyce, MRCP, PhD,
- Ole-Bjørn Tysnes, MD, PhD,
- Jonathan R. Evans, MRCP, PhD,
- David P. Breen, MRCP, PhD,
- Karol Estrada, PhD,
- Claire E. Wegel, MPH,
- Fabrice Danjou, MD, PhD,
- David K. Simon, MD, PhD,
- Bernard Ravina, MD,
- Mathias Toft, MD, PhD,
- Peter Heutink, PhD,
- Bastiaan R. Bloem, MD, PhD,
- Daniel Weintraub, MD,
- Roger A. Barker, MRCP, PhD,
- Caroline H. Williams-Gray, MRCP, PhD,
- Bart P. van de Warrenburg, MD, PhD,
- Jacobus J. Van Hilten, MD, PhD,
- Clemens R. Scherzer, MD,
- Andrew B. Singleton, PhD and
- Mike A. Nalls, PhD
- 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.
- Correspondence
Dr. Nalls nallsm{at}mail.nih.gov
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).
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.
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.
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.
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
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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NONE
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NONE
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Research Support, Academic Entities:NONE
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:(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
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:NONE
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:NONE
Patents:NONE
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:Former employee of Biogen (3 years) Current employee of Biomarin (6 months)
Speakers' Bureaus:NONE
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:NONE
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:NONE
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:NONE
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:NONE
Patents:NONE
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:NONE
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:NONE
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:Michael J Fox Foundation for Parkinson's Disease Research, The Foundation for Peripheral Neuropathy
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:NONE
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:NONE
Patents:NONE
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:NONE
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:NONE
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:NONE
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:(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
Funding for travel or speaker honoraria:NONE
Editorial Boards:(1) Parkinson Study Group Executive Committee member (non-profit); travel expenses paid for attending the annual meeting. (2) Steering Committee for the
Patents:NONE
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:(1) Lysosomal Therapeutics, Inc (commercial); consultant for clinical product development (2) Cerevance, Inc. (commercial); Consultant for clinical trial
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:(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, Academic Entities:(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, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:(1) Weston Brain Institute Advisor Fellowship (2) National Parkinson Foundation Community Grant Award for wellness programs
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:Commercial: Voyager Therapeutics Non Profit: Michael J Fox Foundation
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:NONE
Patents:NONE
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:Voyager Therapeutics and Praxis Precision Medicine
Speakers' Bureaus:NONE
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:NIH, DOD, Michael J Fox Foundation
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:Michael J Fox Foundation
License Fee Payments, Technology or Inventions:Commercial - Voyager Therapeutics and Praxis Precision Medicine
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:NONE
Funding for travel or speaker honoraria:NONE
Editorial Boards:Speaker honoraria from Roche.
Patents:Editorial board member of PLOS One, Frontiers Neurology, Case Reports in Neurological Medicine
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:NONE
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:Research grants from the Research Council of Norway, Regional Health Authority South-Eastern Norway
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:Research grants from the Michael J. Fox Foundation, Norwegian Parkinson Research Fund
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:NONE
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:NONE
Patents:NONE
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:Commercial entity Neuron23 LLC
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:NONE
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:NONE
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:(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);
Funding for travel or speaker honoraria:NONE
Editorial Boards:(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)
Patents:(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).
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:Zambon (commercial entity)
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:(1) UCB (commercial entity); (2) AbbVie (commercial entity); (3) Verily (commercial entity).
Research Support, Academic Entities:(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, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:(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)
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:Commercial - honoraria for consultancy from Acadia, Alkahest, CHDI Foundation, Clintrex LLC, F. Hoffmann-La Roche Ltd and Sunovion Non-profit - CHDI, ADCS, ATRI
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:NONE
Patents:Associate Editor for Movement Disorders Journal
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:NONE
Other activities:NONE
Clinical Procedures or Imaging Studies:Licensing fees from the University of Pennsylvania for the QUIP and QUIP-RS
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:NINDS, P50 NS053488, Investigator, 2007-2018 NIA, U19 AG10483-22, DSMB Chair, 2013-
Research Support, Foundations and Societies:U. of Pennsylvania internal grant funding
Stock/Stock Options/Board of Directors Compensation:Michael J. Fox Foundation for Parkinson's Research, PI,
License fee payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:Licensing fees from the University of Pennsylvania for licensing of Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease.
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
Expert testimony for defense in 2012-2017 in three lawsuits related to impulse control disorders or antipsychotic use in Parkinson's disease
Gifts:NONE
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:NONE
Patents:Co-Editor in Chief, Journal of Neurology. Editorial Boaard of Journal of Parkinson's Disease. .
Publishing Royalties:NONE
Employment, Commercial Entity:Neuroscience at a glance. 5th Edition. 2012.Wiley.
Consultancies:NONE
Speakers' Bureaus:Sana; BlueRock; Nova Nordisk; FCDI; Cellino;LCT
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:NONE
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:I have recieved funding from the EU; Parkinson's UK; CHDI; Cure PD; Rosetrees trust; Michael J Fox Foundation; Wellcome Trust; MRC.
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:NONE
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:NONE
Patents:Movement Disorders, Editorial Board Member, 2015 to present.
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:NONE
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:(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, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:(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
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:NONE
Funding for travel or speaker honoraria:NONE
Editorial Boards:Travel stipends from the Parkinson and Movement Disorder Society and European Academy of Neurology for lectures at their international meetings, non-profit
Patents: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.
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:NONE
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:(1) Bioblast Pharma
Research Support, Academic Entities:ZonMW, 9003037604 and 733051066, funding agency, 2016 - present
Research Support, Foundations and Societies:(1) Radboud University Medical Center, Nijmegen, the Netherlands
Stock/Stock Options/Board of Directors Compensation:Hersenstichting Gossweiler Foundation
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:NONE
Funding for Travel or Speaker Honoraria:Partial funding Travel/congres expences by ABBVIE
Editorial Boards:NONE
Patents:NONE
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:NONE
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:NONE
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:International Parkinson Disease Foundation Van Alkemade - Keuls Foundation AbbVie
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:Sanofi Scientific Advisory Committee for MOVES-PD Phase 2 Clinical Trial of Venglustat in GBA-PD
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:NONE
Patents:2008 - present Editorial Board Member, Biomarkers in Medicine 2011 - present Editorial Board Member, Neurogenetics
Publishing Royalties: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
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:AMGEN
Other activities:NONE
Clinical Procedures or Imaging Studies:C.R.S. has previously had scientific collaborations with Pfizer, Opko, Proteome Sciences.
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities: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, Foundations and Societies:Harvard NeuroDiscovery Center
Stock/Stock Options/Board of Directors Compensation: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
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:NONE
Funding for travel or speaker honoraria:NONE
Editorial Boards:(1) 23andMe, travel payment
Patents:Serve on: Annals of Neurology Lancet Neurology Neurogenetics Neurobiology of Disease Neurodegenerative Diseases Brain Journal of Parkinson's Disease
Publishing Royalties:Patent pending for panel of markers to diagnose stroke
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:NONE
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:NIH Intramural funding Department of Defense, W81XWH-09-2-0128, PI, 2009-2011
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:NONE
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE
Gifts:NONE
Funding for Travel or Speaker Honoraria:NONE
Editorial Boards:NONE
Patents:NONE
Publishing Royalties:NONE
Employment, Commercial Entity:NONE
Consultancies:NONE
Speakers' Bureaus:NONE
Other Activities:NONE
Clinical Procedures or Imaging Studies:NONE
Research Support, Commercial Entities:NONE
Research Support, Government Entities:NONE
Research Support, Academic Entities:NIH employee (2005-current)
Research Support, Foundations and Societies:NONE
Stock/Stock Options/Board of Directors Compensation:NONE
License Fee Payments, Technology or Inventions:NONE
Royalty Payments, Technology or Inventions:NONE
Stock/Stock Options, Research Sponsor:NONE
Stock/Stock Options, Medical Equipment & Materials:NONE
Legal Proceedings:NONE
NONE