Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.
Keywords: Smoking; alcohol; coffee; Parkinson's disease; Mendelian randomisation
Parkinson's disease (PD) is considered as a multifactorial disease, involving genetic susceptibility and environmental factors [[
Mendelian randomisation (MR) is a form of instrumental variable analysis that uses genetic variants associated with an exposure as instruments to estimate its causal association with a disease [[
As part of the COmprehensive Unbiased Risk factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used two-sample MR to examine the association of three lifestyle behaviours (smoking, alcohol drinking, coffee drinking) with PD, and assessed whether MR findings are robust in analyses addressing the potential for survival and incidence-prevalence biases.
MR uses genetic variants, mainly single nucleotide polymorphisms (SNPs), associated with an exposure to estimate its causal effect on an outcome. For SNPs to be valid instruments, three assumptions must be verified: i) SNPs should be associated with the exposure (IV1 assumption); ii) SNPs should not be directly associated with the outcome except through the exposure (IV2 assumption); and iii) SNPs should not be associated with unmeasured confounders of the exposure-outcome association (i.e., no horizontal pleiotropy, IV3 assumption) [[
In two-sample MR, summary statistics (effect size estimates and standard errors [SE]) for the SNP-exposure and SNP-outcome associations, required to estimate the causal exposure-outcome association, come from two independent samples.
We used summary statistics from a GWAS (NeuroChip) [[
In each study, the frequency of SNPs was compared in cases and controls under an additive model using logistic regression adjusted for sex and the first four principal components. We meta-analysed summary statistics from the 23 GWAS (European ancestry: 7,369 cases, 7,018 controls) using a fixed (I
Individual studies within each genome-wide association study had received approval from a relevant institutional review board from their country, and informed consent was obtained from participants or from a caregiver, legal guardian, or other proxy.
We used summary statistics (betas, SEs) from published GWAS in individuals of European descent to select SNPs associated with exposures of interest at a genome-wide significant threshold (p < 5×10
The GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN) provided summary statistics for smoking initiation (n = 1,232,091, 203 SNPs) and for the number of alcohol drinks per week (n = 941,280, 71 SNPs) in participants of European descent [[
Information on smoking status was missing in several studies from Courage-PD; therefore, we were not able to run analyses stratified by smoking status and to examine the role of SNPs associated with smoking heaviness or age at smoking cessation or initiation in smokers [[
We used a GWAS on self-reported bitter and sweet beverage consumption, including coffee (European ancestry, n = 370,000, 11 SNPs) [[
Statistical analyses were performed using the TwoSampleMR, MRPRESSO, and simex R packages (R Foundation for Statistical Computing, Vienna, Austria). P-values are two-sided. We examined three main exposures (smoking initiation, alcohol drinking, coffee drinking). To account for multiple testing, we used a conservative approach and applied a Bonferroni corrected significance level of 0.017 (i.e., 0.05/3). P-values≤0.05 but > 0.017 were considered as suggestive statistical evidence for an association [[
Only SNPs available in 75%(n = 17) of the studies or more were retained for our analyses. For each SNP, we computed the proportion of the variance of the exposure explained by the SNP (R
For MR analyses of individual SNPs, we used the Wald ratio estimate (exponentiated ratio of the SNP-outcome association to the SNP-exposure association).
Our primary MR analyses based on multiple SNPs were conducted using the random-effects inverse-variance weighted (IVW) method that provides accurate estimates for SNPs that verify IV assumptions. Heterogeneity between genetic instruments was tested using the Cochran's Q-statistic [[
In sensitivity MR analyses, we used other approaches that relax some IV assumptions. The MR-Egger method can detect directional pleiotropy and provides corrected effect estimates but has low power and requires the InSIDE (INstrument Strength Independent of Direct Effect) assumption [[
PD is typically a disease of old age, and survival bias may bias genetic associations and MR estimates in any direction in studies in older populations for exposures that are associated with survival into old age (Supplementary Figure 1) [[
The consortium included prevalent and incident patients. If genetic variants have a stronger effect on survival in PD patients than controls, genetic associations may be biased [[
Finally, we tested for reverse causation by performing a reverse MR analysis where the exposure was PD genetic susceptibility and the outcome was smoking initiation, alcohol, or coffee drinking. We identified top SNPs (and corresponding association estimates) from the largest PD iPDGC GWAS as exposure instrumental variables [[
For each exposure, we computed the proportion of variance explained by the SNPs, the F-statistic as a measure of instrument strength [[
Results can be reproduced using Supplementary Tables 3 and 4; no additional data available.
The associations of SNPs with exposures and PD are shown in Supplementary Tables 3 and 4. Supplementary Table 5 shows the number of SNPs retained for each exposure and F-statistics.
Of the SNPs positively associated with smoking traits, two (1.1%) were positively associated with PD at p < 0.05 for smoking initiation, and five (4.4%) for the lifetime smoking index; six (3.3%) were inversely associated with PD for smoking initiation, and five (4.4%) for the lifetime smoking index (Supplementary Table 3).
Smoking initiation was significantly and inversely associated with PD (OR
Table 1 Effect of genetically-predicted smoking on PD
Exposure Odds ratio (95%CI) Smoking initiation (per 1-SD increase in the prevalence of ever smoking) IVW (p-heterogeneity = 0.39) 0.74 (0.60–0.93) 0.009 Weighted median 0.64 (0.47–0.89) 0.008 Weighted mode 0.58 (0.24–1.42) 0.23 MR Egger (p-pleiotropy = 0.59;= 0.66) 0.59 (0.24–1.45) 0.25 Corrected MR Egger 0.56 (0.22–1.39) 0.26 MR-PRESSO (p-pleiotropy = 0.24) – – Lifetime smoking index (per 1-unit)a IVW (p-heterogeneity = 0.007) 0.54 (0.29–1.00) 0.050 Weighted median 0.37 (0.16–0.84) 0.017 Weighted mode 0.29 (0.06–1.34) 0.12 MR Egger (p-pleiotropy = 0.93; = 0.64) 0.60 (0.05–6.77) 0.68 Corrected MR Egger 0.60 (0.06–6.47) 0.68 MR-PRESSO (p-pleiotropy = 0.010, p-distortion = 0.77)b 0.51 (0.29–0.89) 0.021
CI, confidence interval; IVW, inverse variance weighted.
In sensitivity analyses, there was a suggestive inverse association for the lifetime smoking index (OR
Both for smoking initiation and the lifetime smoking index, associations tended to be stronger in younger individuals (smoking initiation: OR
Graph: Fig. 1 Forest plot showing MR estimates for the association of smoking initiation and a lifetime smoking index with PD, overall and after stratification by age at study and disease duration in cases. OR, odds ratio; CI, confidence interval.
Of the SNPs positively associated with alcohol drinking, two (3.2%) were positively and three (4.8%) were inversely associated with PD at p < 0.05 (Supplementary Table 3).
There was no significant association between alcohol drinking and PD (OR
Table 2 Effect of genetically-predicted alcohol drinking on PD
Exposure Odds ratio (95%CI) Alcohol drinking (per 1-SD increase of ln(drinks per week)) IVW (p-heterogeneity = 0.062) 0.68 (0.39–1.18) 0.17 Weighted median 0.86 (0.42–1.75) 0.67 Weighted mode 0.86 (0.41–1.77) 0.68 MR Egger (p-pleiotropy = 0.94; = 0.96) 0.70 (0.30–1.61) 0.40 MR-PRESSO (p-pleiotropy = 0.042, p-distortion = 0.73a) 0.77 (0.46–1.29) 0.33 Alcohol drinking: after exclusion of 2 SNPs associated with coffee drinking: rs1260326 and rs2472297 (per 1-SD increase of ln(drinks per week) IVW (p-heterogeneity = 0.11) 0.78 (0.45–1.35) 0.37 Weighted median 0.88 (0.44–1.76) 0.72 Weighted mode 0.85 (0.46–1.58) 0.61 MR Egger (p-pleiotropy = 0.98; = 0.96) 0.78 (0.34–1.78) 0.56 MR-PRESSO (p-pleiotropy = 0.089) – –
CI, confidence interval; IVW, inverse variance weighted.
MR analyses using a single SNP in the ADH1B gene (rs1229984) showed no association with PD (OR
Of the SNPs positively associated with coffee drinking, one (9.1%) was positively, and another (9.1%) was inversely associated with PD at p < 0.05 (Supplementary Table 3).
There was a positive and non-statistically significant association of genetically-predicted coffee drinking with PD (OR
Table 3 Effect of genetically-predicted coffee drinking on PD
Exposure Odds ratio (95%CI) Coffee drinking (per ln(cups per day)) IVW (p-heterogeneity = 0.017) 1.69 (0.51–5.63) 0.40 Weighted median 1.51 (0.50–4.51) 0.47 Weighted mode 1.45 (0.52–4.03) 0.50 MR Egger (p-pleiotropy = 0.73; = 0.97) 2.50 (0.21–29.59) 0.49 MR-PRESSO (p-pleiotropy = 0.035, p-distortion = 0.86)a 1.86 (0.67–5.11) 0.26 Coffee drinking: after exclusion of 2 SNPs associated with alcohol drinking: rs1260326 and rs2472297 (per ln(cups per day)) IVW (p-heterogeneity = 0.053) 1.09 (0.26–4.45) 0.91 Weighted median 1.06 (0.32–3.53) 0.93 Weighted mode 1.11 (0.31–4.01) 0.88 MR Egger (p-pleiotropy = 0.35; = 0.96) 3.86 (0.22–66.63) 0.38 MR-PRESSO (p-pleiotropy = 0.12) – –
CI, confidence interval; IVW, inverse variance weighted.
MR analyses based on SNPs in two genes that are known to play an important role in caffeine metabolism (AHR-rs4410790, CYP1A2-rs2472297) showed no association with PD (rs4410790: OR
Supplementary Table 8 shows the SNPs and association estimates used for reverse MR analyses. Table 4 shows the results of reverse MR analyses. There was no association between genetic liability toward PD and smoking or coffee drinking. For alcohol drinking, genetic liability toward PD was positively associated with alcohol drinking using the IVW method. MR-PRESSO identified 5 outliers; the corrected MR estimate after excluding these outliers was still in favour of a positive association.
Table 4 Reverse Mendelian randomisation using PD-associated SNPs from iPDGC [[
Method OR (95%CI) p-het. p-pleio. Smoking initiation 64 SNPs IVW 1.01 (0.99–1.02) 0.18 < 0.001 Weighted median 1.01 (0.99–1.02) 0.36 Weighted mode 1.01 (0.99–1.03) 0.35 MR-Egger 1.02 (0.99–1.05) 0.15 0.36 MR-PRESSO – – < 0.001a Lifetime smoking index 65 SNPs IVW 1.00 (0.99–1.01) 0.83 < 0.001 Weighted median 1.00 (0.99–1.01) 0.38 Weighted mode 0.99 (0.98–1.01) 0.092 MR-Egger 1.01 (0.99–1.02) 0.34 0.23 MR-PRESSO 1.00 (0.99–1.01) 0.56 < 0.001b Alcohol drinking 64 SNPs IVW 1.02 (1.01–1.03) 0.002 < 0.001 Weighted median 1.01 (0.99–1.02) 0.14 Weighted mode 1.01 (0.99–1.02) 0.21 MR-Egger 1.02 (0.99–1.04) 0.097 0.85 MR-PRESSO 1.01 (1.00–1.02) 0.042 < 0.001c Coffee drinking 65 SNPs IVW 1.00 (0.99–1.01) 0.15 < 0.001 Weighted median 1.00 (0.99–1.01) 0.82 Weighted mode 1.00 (0.99–1.01) 0.65 MR-Egger 1.00 (0.99–1.01) 0.69 0.21 MR-PRESSO 1.00 (0.99–1.01) 0.25 < 0.001d
OR, odds ratio per 1-unit increase in log odds of the prevalence of PD; IVW, inverse-variance weighted (random-effect); CI, confidence interval; p-het., p for heterogeneity (IVW); p-pleio., p for pleio-tropy (MR-Egger and MR-PRESSO).
Based on data from the Courage-PD consortium and after exclusion of samples overlapping with iPDGC, our findings add further evidence in favour of an inverse association between smoking initiation and PD but not for alcohol and coffee drinking.
According to observational studies, ever smokers have a ∼40%reduced risk of developing PD [[
Previous MR studies examined the association between smoking and PD using iPDGC data. One study (9,581 cases, 33,245 controls) assessed several risky behaviours in relation with PD [[
Our study replicates these findings and add further evidence in favour of an association between smoking initiation and lower PD risk; in addition, our findings show that genetic liability toward PD is not associated with smoking initiation which does not support the hypothesis of reverse causation for smoking. We further show that survival into old age and incidence-prevalence bias are unlikely explanations for the inverse association between smoking and PD. Since smoking is a major risk factor of mortality, differential survival could potentially bias the association between smoking-related SNP and PD; however, the observation that associations in younger participants were consistent with those seen overall is against this hypothesis and supports an association between smoking and PD [[
The consistency of MR findings with those from traditional epidemiologic studies and reports of smoking-by-gene interactions [[
Previous randomised clinical trials of nicotine for motor symptoms in PD failed to show an effect [[
A meta-analysis of the relation between alcohol and PD reported an inverse association in case-control studies but not in cohort studies, with marked heterogeneity across studies [[
A previous MR study that examined several risky behaviours in relation with PD using iPDGC data (9,581 cases, 33,245 controls) did not provide evidence in favour of an association for the number of drinks per week (70 SNPs; OR = 1.15, 95%CI = 0.87–1.53) or alcohol consumption (7 SNPs; OR = 1.39, 95%CI = 0.11–17.56) [[
Alternatively, reverse MR showed that genetic liability toward PD is positively associated with alcohol drinking, thus suggesting that persons at higher PD risk are more prone to drink alcohol, independently of whether they actually develop PD. This finding warrants further investigation and replication in further studies.
Previous studies, both case-control and cohort, have shown an inverse association between coffee drinking or caffeine intake and PD, with a dose-effect relationship, that was present after adjustment for smoking or in never-smokers [[
A previous MR study that assessed several risky behaviours in relation with PD using iPDGC data (9,581 cases, 33,245 controls) did not provide evidence in favour of an association for the number of coffee cups per day (4 SNPs; OR = 1.03, 95%CI = 0.65–1.63). We did not find a significant association with coffee drinking, but given the low power of the study to detect an association with this exposure, we cannot draw firm conclusions. However, we did find that genetic liability toward PD was not associated with coffee drinking which does not support the hypothesis of reverse causation for coffee drinking.
Strengths of this study include the assessment of several lifestyle behaviours and use of data from a large consortium in which PD cases were carefully assessed by experienced movement disorders specialists. The MR design represents another strength as it avoids bias from reverse causation and confounding [[
The main limitation of our study pertains to its statistical power. Our power calculations showed that our sample size was sufficient to detect ORs in the range of 0.4–0.6 for a type-1 error rate of 1.7%to 5%, for smoking and alcohol but not for coffee drinking. The highest power was noted for smoking initiation; the study was underpowered to detect weaker associations for coffee and alcohol drinking, hence limiting our ability to draw firm conclusions for these exposures. Please note that our study examined a limited number of exposures (selected a priori based on existing literature) and is not exploratory, and that the Bonferroni correction is conservative. Our aim was to assess whether MR findings were consistent with those from observational studies using different sets of genetic instruments and methods, and to perform subgroup sensitivity analyses to examine the robustness of our findings. One limitation of our analyses for smoking is that we were not able to stratify analyses by smoking status and to compare results in ever and never smokers using genetic instruments for smoking intensity or cessation [[
Using an independent dataset, our study confirms previous MR findings adds further evidence in favour of a protective effect of smoking on PD and shows that this association is not explained by survival or incidence-prevalence bias. For alcohol and coffee drinking, larger studies and stronger genetic instruments are needed.
The number of PD cases is predicted to double between 2015–2040 [[
Sophia N Pchelina (Saint Petersburg, Russia), Thomas Brücke (Wien, Austria), Marie-Anne Loriot (Paris, France), Claire Mulot (Paris, France), Yves Koudou (Villejuif, France), Jean-Christophe Corvol (Paris, France), Georgia Xiromerisiou (Larissa, Greece), Christos Koros (Athens, Greece), Matina Maniati (Athens, Greece), Maria Bozi (Athens, Greece), Micol Avenali (Pavia, Italy), Margherita Canesi (Milan, Italy), Giorgio Sacilotto (Milan, Italy), Michela Zini (Milan, Italy), Roberto Cilia (Milan, Italy), Francesca Del Sorbo (Milan, Italy), Nicoletta Meucci (Milan, Italy), Letizia Straniero (Milan, Italy), Rosanna Asselta (Milan, Italy), Radha Procopio (Catanzaro, Italy), Aldo Quattrone (Catanzaro, Italy), Manabu Funayama (Tokyo, Japan), Aya Ikeda (Tokyo, Japan), Takashi Matsushima (Tokyo, Japan), Yuanzhe Li (Tokyo, Japan), Hiroyo Yoshino (Tokyo, Japan), Zied Landoulsi (Luxembourg, Luxembourg), Rubén Fernández-Santiago (Barcelona, Spain), Nicholas Wood (London, UK), Huw R Morris (London, UK).
We thank the UK Biobank, GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN), the Bitter and sweet beverage consumption GWAS consortium and the Psychiatric Genetics Consortium for providing summary statistics for these analyses.
This study used data from the Courage-PD consortium, conducted under a partnership agreement between 35 studies. The Courage-PD consortium is supported by the EU Joint Program for Neurodegenerative Disease research (JPND; https://
CD is the recipient of a doctoral grant from Université Paris-Saclay, France.
MS was supported by the grants from the German Research Council (DFG/SH 599/6-1), MSA Coalition, and Michael J Fox Foundation (USA Genetic Diversity in PD Program: GAP-India Grant ID: 17473).
ABS, DGH, and CE are funded by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, project ZO1 AG000949.
ER is funded by the Canadian Consortium on Neurodegeneration in Aging.
SK is funded by MSWA.
PT is the recipient of an Estonian Research Council Grant PRG957.
EMV is funded by the Italian Ministry of Health (Ricerca Corrente 2021).
SB and JC are supported by grants from the National Research Foundation of South Africa (Grant Number: 106052); the South African Medical Research Council (Self-Initiated Research Grant); and Stellenbosch University, South Africa; they also acknowledge the support of the NRF-DST Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town.
PP and MDF have received funding from the Spanish Ministry of Science and Innovation (SAF2013-47939-R).
KW and NLP are funded by the Swedish Research Council, grant numbers K2002-27X-14056-02B, 521-2010-2479, 521-2013-2488, 2017-02175.
NLP is funded by the National Institutes of Health, grant numbers ES10758 and AG 08724.
CR is funded by the Märta Lundkvist Foundation, Swedish Brain Foundation, Karolinska Institutet Research Fund.
ACB from the Swedish Brain Foundation, Swedish Research Council, Karolinska Institutet Research Funds.
MT is funded by the Parkinson's UK.
PG GEN sample collection was funded by the MRC and UK Medical Research Council (CEC, KEM).
The sponsors had no role in the study design, data collection, data analysis, data interpretation, the writing of the report, or the decision to submit the paper for publication.
PM reports grants from Fonds National de Recherche (FNR), grants from German Research Council (DFG), during the conduct of the study; and Patrick May is co-founder of MeGeno S.A., Esch-sur-Alzette, Luxembourg, a company for personal genomics.
DRB worked as a staff scientist at Megeno S.A.
ABS reports grants from Department of Defense, during the conduct of the study; grants from Michael J Fox Foundation, outside the submitted work.
WP reports personal fees from Grünenthal, personal fees from AbbVie, personal fees from AOP Orphan, personal fees from Zambon, personal fees and other from Boehringer Ingelheim, personal fees from Stada, personal fees from UCB Pharma, outside the submitted work.
AEL reports personal fees from AbbVie, personal fees from AFFiRis, personal fees from Janssen, personal fees from Biogen, personal fees from Merck, personal fees from Sun Pharma, personal fees from Corticobasal Solutions, personal fees from Sunovion, personal fees from Paladin, personal fees from Lilly, personal fees from Medtronic, personal fees from Theravance, personal fees from Lundbeck, personal fees from Retrophin, personal fees from Roche, personal fees from PhotoPharmics, outside the submitted work.
AB reports grants from France Parkinson + FRC, grants from ANR - EPIG - Agence nationale de recherche, grants from ANR - JPND - Agence nationale de recherche, grants from RDS (Roger de Spoelberch Foundation), grants from France Alzheimer, grants from Institut de France, grants from ANR - EPIG, grants from FMR (maladies rares), outside the submitted work.
JCC reports grants from the Michael J Fox Foundation, Sanofi, and served in advisory boards for Air Liquide, Biogen, Denali, Ever Pharma, Idorsia, Prevail Therapeutic, Theranexus, UCB, outside the submitted work.
MCCH reports grants from France Parkinson, grants from ANR –Agence nationale de recherche, (MetDePaDi, Synapark), grant from ANR –JPND (TransNeuro), Agence nationale de recherche, Grant; grants from Fondation de France, grants from the Michael J Fox Foundation, outside the submitted work.
KB reports grants from MJFF, grants from BMBF, personal fees from Zambon, UCB, Abbvie, grants from University of Tuebingen, outside the submitted work.
EMV reports speaking honoraria from Zambon; served as expert panelist for the International Parkinson and Movement Disorder Society; serves as Associate Editor of Journal of Medical Genetics, Section Editor of Pediatric Research, Member of the Editorial Board of Movement Disorders Clinical Practice; grants from the Italian Ministry of Health, CARIPLO Foundation, Pierfranco and Luisa Mariani Foundation, outside the submitted work.
NH reports grants from - Japan Agency for Medical Research and Development (AMED), grants from - Japan Society for the Promotion of Science (JSPS), grants from - Ministry of Education Culture,Sports,Science and Technology Japan; Grant-in-Aid for Scientific Research on Innovative Areas, personal fees and other from Dai-Nippon Sumitomo Pharma Co., Ltd, personal fees and other from Takeda Pharmaceutical Co., Ltd., personal fees and other from Kyowa Kirin Co., Ltd., personal fees and other from GSK K.K, personal fees and other from Nippon Boehringer Ingelheim, Co., Ltd, personal fees and other from FP Pharmaceutical Corporation, personal fees and other from Eisai Co., Ltd., personal fees and other from Kissei Pharmaceutical Company, personal fees and other from Nihon Medi-physics Co., Ltd, personal fees and other from Novartis Pharma K.K, personal fees and other from Biogen Idec Japan Ltd, personal fees and other from AbbVie, from Medtronic, Inc., other from Boston Scientific Japan, personal fees and other from Astellas Pharma Inc., grants and other from Ono Pharmaceutical Co., Ltd, other from Nihon Pharmaceutical Co., Ltd, other from Asahi Kasei Medical Co., Ltd, other from Mitsubishi Tanabe Pharma Corporation, personal fees and other from Daiichi Sankyo Co., other from OHARA Pharmaceutical Co., Ltd, other from Meiji Seika Pharma, personal fees from Sanofi K.K., personal fees from Pfizer Japan Inc., personal fees from Alexion Pharmaceuticals, personal fees from Mylan N.V, personal fees from MSD K.K, personal fees from Lund Beck Japan, other from Hisamitsu Pharmaceutical Co., Inc, outside the submitted work.
KN reports grants from - Japan Society for the Promotion of Science (JSPS), outside the submitted work.
PK reports other from Centre Hospitalier de Luxembourg; University of Luxembourg, grants from Fonds National de Recherche (FNR), from null, outside the submitted work.
BPCW reports grants from ZonMW, grants from Hersenstichting, grants from uniQure, other from uni-Qure, grants from Gossweiler Fund, grants from Radboud university medical centre, outside the submitted work.
BRB reports grants from Netherlands Organization for Health Research and Development, grants from Michael J. Fox Foundation, grants from Parkinson Vereniging, grants from Parkinson Foundation, grants from Gatsby Foundation, grants from Verily Life Sciences, grants from Horizon 2020, grants from Topsector Life sciences and Health, grants from Stichting Parkinson Fonds, grants from UCB, grants from Abbvie, during the conduct of the study; personal fees from Biogen, personal fees from Abbvie, personal fees from Walk with Path, perso-nal fees from UCB, personal fees from Abbvie, personal fees from Zambon, personal fees from Bial, personal fees from Roche, outside the submitted work; and Serves as editor-in-chief of the Journal of Parkinson's Disease and serves on the editorial board of Practical Neurology and Digital Biomarkers.
MT (M.Toft) reports grants from Research Council of Norway, during the conduct of the study; grants from South-Eastern Norway Regional Health Authority, grants from Michael J. Fox Foundation, outside the submitted work.
LP reports grants from Norwegian Health Association, grants from South-Eastern Norway Regional Health Authority, outside the submitted work.
JJF reports grants from GlaxoSmithKline, grants from Grunenthal, grants from Fundação MSD (Portugal), grants from TEVA, grants from MSD, grants from Allergan, grants from Novartis, grants from Medtronic, grants from GlaxoSmithKline, grants from Novartis, grants from TEVA, grants from Lundbeck, grants from Solvay, grants from BIAL, grants from Merck-Serono, grants from Merz, grants from Ipsen, grants from Biogen, grants from Acadia, grants from Allergan, grants from Abbvie, grants from Sunovion Pharmaceuticals, personal fees from Faculdade de Medicina de Lisboa, personal fees from CNS - Campus Neurológico Sénior, personal fees from BIAL, personal fees from Novartis, outside the submitted work.
ET received honoraria for consultancy from TEVA, Bial, Prevail Therapeutics, Boehringer Ingelheim, Roche and BIOGEN and has received funding for research from Spanish Network for Research on Neurodegenerative Disorders (CIBERNED)- Instituto Carlos III (ISCIII), and The Michael J. Fox Foundation for Parkinson's Research (MJFF).
KW reports grants from Swedish Research Council, during the conduct of the study.
NLP reports grants from Swedish Research Council, during the conduct of the study.
AP reports grants from Parkinsonfonden (The Swedish Parkinson Foundation), grants from ALF (Swedish Government), grants from Region Skåne, Sweden, grants from Hans-Gabriel och Trolle Wachtmeister Stiftelse för Medicinsk Forskning, Sweden, during the conduct of the study; personal fees from Elsevier, outside the submitted work.
MT (M. Tan) reports grants from Parkinson's UK, other from Michael J Fox Foundation, other from University College London, outside the submitted work.
RK reports grants from Fonds National de Recherche (FNR), grants from German Research Council (DFG), non-financial support from Abbvie, Zambon, during the conduct of the study; personal fees from University of Luxembourg; Luxembourg Institute of Health; Centre Hospitalier de Luxembourg, grants from Fonds National de Recherche, Luxembourg (FNR), grants from Fonds National de Recherche, Luxembourg (FNR), grants from Fonds National de Recherche (FNR), Luxembourg/German Research Council (DFG), grants from Fonds National de Recherche, Luxembourg (FNR), personal fees from Desitin/Zambon, personal fees from Abbvie GmbH, personal fees from Medtronic GmbH, outside the submitted work.
TG reports personal fees from UCB Pharma, personal fees from Novartis, personal fees from Teva, personal fees from MedUpdate, grants from The Michael J Fox Foundation for Parkinson's Research, grants from Bundesministerium für Bildung und Forschung (BMBF), grants from Deut-sche Forschungsgemeinschaft (DFG), other from "Joint Programming for Neurodegenerative Diseases" (JPND) program, funded by the European Commission, outside the submitted work; in addition, Dr. Gasser has a patent Patent Number: EP1802749 (A2) KASPP (LRRK2) gene, its production and use for the detection and treatment of neurodegenerative disorders issued.
By Cloé Domenighetti; Pierre-Emmanuel Sugier; Ashwin Ashok Kumar Sreelatha; Claudia Schulte; Sandeep Grover; Océane Mohamed; Berta Portugal; Patrick May; Dheeraj R. Bobbili; Milena Radivojkov-Blagojevic; Peter Lichtner; Andrew B. Singleton; Dena G. Hernandez; Connor Edsall; George D. Mellick; Alexander Zimprich; Walter Pirker; Ekaterina Rogaeva; Anthony E. Lang; Sulev Koks; Pille Taba; Suzanne Lesage; Alexis Brice; Jean-Christophe Corvol; Marie-Christine Chartier-Harlin; Eugénie Mutez; Kathrin Brockmann; Angela B. Deutschländer; Georges M. Hadjigeorgiou; Efthimos Dardiotis; Leonidas Stefanis; Athina Maria Simitsi; Enza Maria Valente; Simona Petrucci; Stefano Duga; Letizia Straniero; Anna Zecchinelli; Gianni Pezzoli; Laura Brighina; Carlo Ferrarese; Grazia Annesi; Andrea Quattrone; Monica Gagliardi; Hirotaka Matsuo; Yusuke Kawamura; Nobutaka Hattori; Kenya Nishioka; Sun Ju Chung; Yun Joong Kim; Pierre Kolber; Bart PC van de Warrenburg; Bastiaan R. Bloem; Jan Aasly; Mathias Toft; Lasse Pihlstrøm; Leonor Correia Guedes; Joaquim J. Ferreira; Soraya Bardien; Jonathan Carr; Eduardo Tolosa; Mario Ezquerra; Pau Pastor; Monica Diez-Fairen; Karin Wirdefeldt; Nancy L. Pedersen; Caroline Ran; Andrea C. Belin; Andreas Puschmann; Clara Hellberg; Carl E. Clarke; Karen E. Morrison; Manuela Tan; Dimitri Krainc; Lena F. Burbulla; Matt J. Farrer; Rejko Krüger; Thomas Gasser; Manu Sharma and Alexis Elbaz
Reported by Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author