# Replication of a Novel Parkinson's Locus in a European Ancestry Population

Sandeep Grover, Ashwin Ashok Kumar-Sreelatha, Dheeraj Reddy Bobbili, Patrick May, Cloé Domenighetti, Pierre Emmanuel Sugier, Claudia C. Schulte, Alexis Elbaz, Rejko Krüger, Thomas Gasser, et al.

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► To cite this version:

Sandeep Grover, Ashwin Ashok Kumar-Sreelatha, Dheeraj Reddy Bobbili, Patrick May, Cloé Domenighetti, et al. Replication of a Novel Parkinson's Locus in a European Ancestry Population. Movement Disorders, 2021, 36 (7), pp.1689-1695. 10.1002/mds.28546. hal-03329880

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Distributed under a Creative Commons Attribution 4.0 International License
BRIEF REPORTS

Replication of a Novel Parkinson's
Locus in a European Ancestry
Population

Sandeep Grover, PhD,¹†

Ashwin Ashok Kumar-Sreelatha, MSc, MTech,¹†

Dheeraj R. Bobbili, PhD,² Patrick May, PhD,²

Cloé Domenighetti, MSc,³ Pierre-Emmanuel Sugier, PhD,³

Claudia Schulte, PhD,⁴ COURAGE-PD Consortium,‡

Alexis Elbaz, MD, PhD,³ Rejko Krüger, MD,⁵,⁶,⁷

Thomas Gasser, MD,⁴ Manu Sharma, PhD,¹*

and COURAGE-PD Consortium‡

¹Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany ²Bioinformatics Core, Luxembourg Centre for Systems Biomedicine (LCSB), Belvaux, Luxembourg ³UVSQ, Univ. Paris-Sud, Inserm, Team « Exposome, Heredity, Cancer, and Health, CESP, Université Paris-Saclay, Villejuif, France ⁴Center of Neurology, and Hertie Institute for Clinical Brain Research, University Hospital, Tübingen, Germany ⁵Translational Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), Belvaux, Luxembourg ⁶Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg ⁷Parkinson Research Clinic, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

*Correspondence to: Dr. Manu Sharma, Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, 72076, Germany; E-mail: manu.sharma@uni-tuebingen.de

†Contributed equally to the work

‡Members of the COURAGE-PD Consortium are listed in the supplementary (Appendix S1)

**Relevant conflicts of interest/financial disclosures:** The authors report no conflicts of interest. C.D. is the recipient of a doctoral grant from the Université Paris-Saclay, France. D.R.B. is currently working as a staff scientist at Megeno S.A. P.M. reports grants from Fonds National de Recherche (FNR), grants from German Research Council (DFG), during the conduct of the study.

**Funding agencies:** This study was funded by the Michael J. Fox Foundation, USA Genetic Diversity in PD Program: GAP-India grant 17473 (M.S.). M.S. was further supported by the grants from the German Research Council (DFG/SH 599/6-1), MSA Coalition, and Michael J. Fox Foundation. This work was also supported by grants from the Luxembourg National Research Fund (FNR) within the PEARL programme (FNR/P13/6682797 to R.K.) and the National Centre for Excellence in Research in Parkinson's Disease (NCER-PD).

**Received:** 15 December 2020; **Revised:** 2 February 2021; **Accepted:** 2 February 2021

Published online 24 March 2021 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.28546

**ABSTRACT:** Background: A recently published

East Asian genome-wide association study of Parkinson's disease (PD) reported 2 novel risk loci, SV2C and WBSCR17.

**Objectives:** The objective of this study were to determine whether recently reported novel SV2C and WBSCR17 loci contribute to the risk of developing PD in European and East Asian ancestry populations.

**Methods:** We report an association analysis of recently reported variants with PD in the COURAGE-PD cohort (9673 PD patients; 8465 controls) comprising individuals of European and East Asian ancestries. In addition, publicly available summary data (41,386 PD patients; 476,428 controls) were pooled.

**Results:** Our findings confirmed the role of the SV2C variant in PD pathogenesis (rs246814, COURAGE-PD $P_{European} = 6.64 \times 10^{-4}$, pooled PD $P = 1.15 \times 10^{-11}$). The WBSCR17 rs9638616 was observed as a significant risk marker in the East Asian pooled population only ($P = 1.16 \times 10^{-8}$).

**Conclusions:** Our comprehensive study provides an up-to-date summary of recently detected novel loci in different PD populations and confirmed the role of SV2C locus as a novel risk factor for PD irrespective of the population or ethnic group analyzed. © 2021 The Authors. *Movement Disorders* published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

**Key Words:** ethnic transferability; synaptic vesicle; dopamine transmission

Parkinson's disease (PD) is a complex neurodegenerative disease characterized by the predominant loss of nigrostriatal dopaminergic neurons and the formation of Lewy bodies.¹ The majority of underlying genetic causes for both familial and sporadic forms of PD have been identified in the European ancestry population.²⁻⁴ These discoveries, nonetheless, have considerably improved our understanding of PD, yet there remains a concern for genetic transferability of these loci in other ethnically distinct populations.⁵,⁶ To unravel the genetic spectrum of PD, it is essential to catalogue the genetic architecture of PD in ethnically diverse populations.

In a recent study Foo et al performed a large genome-wide association study (GWAS) in PD patients of East Asian ancestry.⁶ The study not only replicated 9 loci previously reported in European populations but also discovered 2 novel loci (SV2C and WBSCR17). SV2C encodes a synaptic vesicle protein known to be involved in
dopamine transmission with a role in PD, and WBSCR17 encodes an N-acetylgalactosaminyltransferase enzyme with a potential role in membrane trafficking.⁷,⁸ However, it is critical to replicate the newly reported loci in different independent populations, given the variability in allele frequencies, linkage disequilibrium (LD) patterns, and effect estimates.⁵

Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) is one such collaborative initiative, which aims to uncover the complex genetic architecture of PD in different ethnic groups including European and East Asian ancestry populations.⁹ In the present article, we aimed to replicate the findings for the recently detected novel loci SV2C and WBSCR17 using the newly generated COURAGE-PD data set and provide an up-to-date summary by pooling different publicly available PD data sets.

# Methods

## COURAGE-PD Project

As part of the COURAGE-PD project, 27,538 individuals comprising 35 independent cohorts were genotyped with the NeuroChip.⁹ Quality control (QC) was conducted independently for each cohort according to standard procedures (Supplementary methods). This was followed by imputation using the HRC reference panel. After conducting QC and imputation procedures, a total of 9673 PD cases and 8465 controls comprising 26 independent cohorts across 17 countries were finally included in the present study (Supplementary methods, eTable S1). The association analysis was performed in each cohort assuming an additive genetic model adjusted for sex and the first 4 principal components.¹⁰

## Meta-Analysis of COURAGE-PD and Other PD Data Sets

We employed weighted Z-score meta-analysis of log-odds ratios (ORs) and standard errors (SEs) as implemented in the METAL software to combine summary statistics across all the COURAGE-PD cohorts for the variants identified in the recent East Asian meta-GWAS.¹¹ We also extracted summary data for the novel loci identified in the same study from recently published meta-analysis of GWAS data sets to provide updated pooled summary estimates for rs246814 and rs9638616 stratified by European and East Asian ancestry subpopulations. For the European meta-analysis, we combined the summary statistics from the COURAGE-PD European ancestry data set with those from the largest publicly available PD GWAS of European ancestry comprising of 36,674 PD patients, and 449,056 controls from the International Parkinson's Disease Genetics Consortium (IPDGC), and UK Biobank (UKB)² using the same methodology as described above. For the East

Asian meta-analysis, we combined the summary statistics from the COURAGE-PD East Asian data sets with those reported by Foo et al and Satake et al²,³,⁶ using the same methodology as described above. We considered a Bonferroni-corrected threshold of 1.92 × 10⁻³ (number of independent tests, 26) for a replication study in our COURAGE-PD data set (eTable 2). We further considered a significance level of P < 1 × 10⁻⁵ as evidence of suggestive association in the pooled meta-analysis of the latest large publicly available data sets (http://www.pdgene.org/methods).

## Computation of Polygenic Risk Scores in COURAGE-PD European Ancestry Data Set

Polygenic risk scores (PRSs) were calculated using 9 of the previously reported 11 East Asian GWAS loci available in the 8916 PD cases and 7617 controls from the COURAGE-PD European ancestry subpopulations. The β values for calculating the PRS were obtained from the previously largest publicly available European ancestry base data set, and weighted PRS profiling was performed in R package PRSice2.² PRS cutoffs for the top and bottom 5% and 10% based on controls were calculated, and numbers of PD cases and controls within each score range were computed to determine the risk difference between the 2 groups using a 2-sided Fisher's exact test.

## AUC/ROC Analysis in COURAGE-PD European Ancestry Data Set

The proportion of the genetic heritability in PD risk explained by single-nucleotide polymorphisms (SNP entered in the PRS model was estimated by calculating Nagelkerke's pseudo R² using the R package fmsb. Receiver operating characteristic (ROC) curves and area under the curve (AUC) estimates were plotted using the R package pROC.

## Regional Association Plots

Regional association plots were drawn for a 5-kb region around the SNPs of interest and the top candidate SNPs by the web-based LocusZoom (http://locuszoom.sph.umich.edu/locuszoom).

# Results

## Meta-Analysis of COURAGE-PD Data Sets

The study population included 9673 PD cases and 8465 controls. The frequencies of the novel variants in our data set are 8.3% and 31.5% for SV2C rs246814 T and WBSCR17 rs9638616 T, respectively. A single-marker analysis showed a significant overrepresentation of SV2C rs246814 T-allele in PD cases compared with controls in the European ancestry population data set
<table><caption>TABLE 1. A meta-analysis of novel loci detected in a recent study in the latest PD data sets with European ancestry</caption><thead><tr><th>SNP</th><th>Chr</th><th>Pos</th><th>EA</th><th>OA</th><th>Nearest gene</th><th>PD cases (n)</th><th>Controls (n)</th><th>OR (95% CI)</th><th>β</th><th>SE</th><th>P</th><th>I2, %</th><th>Het P</th></tr></thead><tbody><tr><td colspan="14"><strong>European ancestry</strong></td></tr><tr><td>rs246814</td><td>5</td><td>75,599,208</td><td>T</td><td>C</td><td>SV2C</td><td>42,590</td><td>456,673</td><td>1.124 (1.069–1.181)</td><td>0.1170</td><td>0.0254</td><td>4.07 × 10<sup>-6</sup></td><td>0.0</td><td>0.3313</td></tr><tr><td>rs9638616</td><td>7</td><td>70,750,493</td><td>T</td><td>G</td><td>WBSCR17</td><td>16,715</td><td>13,469</td><td>1.013 (0.975–1.052)</td><td>0.0130</td><td>0.0193</td><td>0.502</td><td>0.0</td><td>0.7118</td></tr></tbody></table>

β, Regression coefficient; CI, confidence interval; EA, effect allele; OA, other allele; OR, odds ratio; standard error of β; SNP, single-nucleotide polymorphism.

<figure><img src="image_3.png" /><figcaption>FIG. 1. (A) Polygenic risk score distribution in COURAGE-PD data set using recently reported genome-wide significant SNPs by Foo et al (2020). (B) Receiver operator curve (ROC) based on polygenic risk prediction of Parkinson's disease SNPs in COURAGE-PD European-ancestry data set. [Color figure can be viewed at wileyonlinelibrary.com]</figcaption></figure>

(OR<sub>European</sub>, 1.165; 95% CI, 1.067–1.273; P<sub>European</sub> = 6.64 × 10<sup>-4</sup>; eTable 2. On the other hand, we did not observe any association of WBSCR17 rs9638616 T allele with PD in the COURAGE-PD European ancestry data set (OR<sub>European</sub>, 1.020; 95% CI, 0.969–1.073; P<sub>European</sub> = 0.4552; eTable 2). We did not detect the same variant in the COURAGE-PD East Asian data set.

Meta-Analysis of COURAGE-PD and Other PD Data Sets

We further pooled the COURAGE-PD GWAS data set with the available summary statistics of GWASs of PD in European and East Asian ancestry populations (Table 1). Our meta-analysis confirmed the association of SV2C rs246814 in the pooled data set (eTable 3). We
also confirmed the validity of WBSCR17 rs9638616 as a risk marker in the East Asian population (eTable 4).

## Polygenic Risk Scores and AUC/ROC Analysis in COURAGE-PD European Ancestry Data Set

The overall contribution of 9 of the 11 loci in the COURAGE-PD European ancestry data set is shown in eTable 2. The distribution of PRS scores in both PD cases and healthy population controls is shown in Figure 1. Compared with individuals within the bottom 5% and 10% PRS values, individuals with PRS values within the top 5% and 10% values showed 2.30 (95% CI, 1.88–2.81; $P_{European} < 2.2 \times 10^{-16}$) and 1.92 (95% CI, 1.67–2.21; $P_{European} < 2.2 \times 10^{-16}$) fold higher risk in the COURAGE-PD European ancestry data set (Fig. 1A). The variants further explained 1.06% of PD heritability with an AUC of 55.1% (Fig. 1B).

### Regional Association Plots

Regional association plots were drawn for the SV2C locus in both European and East Asian ancestry COURAGE data sets. Although the most significant SNP in the European data set was located in the downstream region of SV2C genes (rs2937736 or Chr5:75636408, $P_{European} = 7.74 \times 10^{-6}$), the most significant SNP in the Asian data set was identified in the nearby *IQGAP2* gene (rs4704337 or chr5:75869457, $P_{Asian} = 0.014$). However, both the variants did not show LD with SV2C rs246814 in the respective data sets.

## Discussion

To the best of our knowledge, this is the first study that comprehensively assessed the role of 2 novel risk loci in different PD populations and confirmed the role of SV2C in PD pathogenesis.

Our findings in the COURAGE-PD European ancestry data set are consistent with the previous largest publicly available meta-analysis of PD in European ancestry data set (IPDGC + UKB; eTable 2). Although the associations observed for SV2C rs246814 T in both data sets did not surpass Bonferroni threshold for genome-wide significance, by pooling the various PD data sets our meta-analysis showed that the variant could improve the genetic prediction of PD risk (Table 1). In contrast, no association was detected for WBSCR17 rs9638616 in the COURAGE-PD and IPDGC+UKB data sets. On the other hand, the meta-analysis of WBSCR17 rs9638616 in a pooled PD population comprising COURAGE-PD and the latest large publicly available PD data sets provided weak evidence of the involvement of WBSCR17 in PD (eTables 3 and 4). However, the effect appeared to be mainly driven by the East Asian subpopulation, as suggested by the presence of high heterogeneity in the observed association.

The SV2C variant (rs246814) was also observed to be in strong LD with a missense variant, p.Asp543Asn (rs32144); $r^2_{European} = 0.99$. It has been further hypothesized that the missense variant may effect N-linked glycosylation of the extracellular or luminal domain of SV2C and possibly modulates dopamine release in basal ganglia and dopaminergic neurons in PD cases.⁷,¹² Our findings thereby suggest p.Asp543Asn (rs32144) as a common putative functional SNP in European and East Asian ancestry populations. The regional association plots further ruled out the role of any nearby genes in driving the association observed in the present study. The predictive value of the top loci in the European ancestry population showed a limited predictive power in the European ancestry population (AUC, 55.1%) compared with the Foo et al study (AUC, 60.4%); see Figure 1.

There were limitations in our study as well. The main limitation of the present study was our inability to adjust for age in the COURAGE-PD data set. This was attributed to the availability of sparse data on age in some of our participating study cohorts. Another limitation could be a lack of adjustment for a study-cohort-specific population substructure. The possibility of a slight over- or underadjustment in some of the study cohorts cannot be ruled out. Nevertheless, the strong association observed for SV2C in our COURAGE-PD data set and retention of the association after pooling our data set with other worldwide data sets provides compelling evidence for the novel locus's role in PD pathogenesis.

In summary, our study showed the relevance of cohorts with different ancestries to test the validity of newly defined PD loci.

**Acknowledgments:** We thank all the subjects who donated their time and biological samples to participate in this study. The COURAGE-PD consortium is 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://www.neurodegenerationres.earch.eu/initiatives/annual-calls-for-proposals/closed-calls/risk-factors-2012/risk-factor-call-results/courage-pd/, grant 01ED1406). Open access funding enabled and organized by Projekt DEAL.

## Author contributions

Grover and Kumar-Sreelatha Ashok contributed equally to this work. Kumar-Sreelatha had full access to all the data in the study and takes responsibility for the integrity of the data. Grover, Kumar-Sreelatha and Bobbili take responsibility for accuracy of the data analysis.

Concept and design: Grover, Sharma.

Acquisition, analysis, or interpretation of data: Grover, Kumar-Sreelatha, Sharma.

Drafting of the manuscript: Grover, Sharma.

Critical revision of the manuscript for important intellectual content: Sharma, May, Elbaz, Domenighetti, Krüger, Gasser.

Statistical analysis: Grover, Kumar-Sreelatha, and Bobbili.

Supervision: Sharma.
## List of Collaborators

**Australia:** Georges D. Mellick (Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia).

**Austria:** Alexander Zimprich (Department of Neurology, Medical University of Vienna, Austria), Thomas Brücke (Verein zur Förderung der wissenschaftlichen Forschung im, Wilhelminenspital (FWFW)) Verein zur Förderung der wissenschaftlichen Forschung im, Wilhelminenspital (FWFW), Walter Pirker (Department of Neurology, Wilhelminenspital, Austria).

**Canada:** Anthony E Lang (Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, Ontario, Canada; Division of Neurology, University of Toronto, Toronto, Ontario, Canada; Krembil Brain Institute, Toronto, Ontario, Canada), Ekaterina Rogaeva (Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada).

**Estonia:** Pille Taba (Department of Neurology and Neurosurgery, University of Tartu, Estonia, and Tartu University Hospital, Estonia), Sulev Koks (Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch and Perron Institute for Neurological and Translational Science, Nedlands, Western Australia, Australia), Mari Muldmaa (Department of Neurology and Neurosurgery, University of Tartu, Estonia, and North Estonian Regional Hospital, Tallinn, Estonia).

**France:** Alexis Brice (Sorbonne Université, Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, AP-HP, Hôpital de la Pitié Salpêtrière, Paris, France), Antouria Mohamed (Université Paris-Saclay, UVSQ, Univ. Paris-Sud, Inserm, Team "Exposome, heredity, cancer and health," CESP, Villejuif, France, Berta Portugal (Université Paris-Saclay, UVSQ, Univ. Paris-Sud, Inserm, Team "Exposome, heredity, cancer and health," CESP, 94807, Villejuif, France), Eugénie Muttez (University of Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, Lille, France), Claire Mulot ICRB Epigenetec, INSERM UMR-S 1138, Université Paris Descartes, France), Jean-Christophe Corvol (Sorbonne Université, Institut du Cerveau et de la Moelle épinière, ICM, Inserm U1127, AP-HP, Hôpital de la Pitié Salpêtrière, Paris, France), Marie-Christine Chartier-Harlin (University of Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, Lille, France), Suzanne Lesage (Sorbonne Université, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France).

**Germany:** Angela B Deutschländer (Department of Neurology, Ludwig Maximilians University of Munich, Germany; Department of Neurology, Max Planck Institute of Psychiatry, Munich, Germany, Department of Neurology; Felix Bartusch (High Performance and Cloud

Computing Group, IT Center (ZDV), University of Tübingen, Tübingen, Germany), Jens Krüger (High Performance and Cloud Computing Group, IT Center (ZDV), University of Tübingen, Tübingen, Germany), Julius Maximilians University of Würzburg, Wuerzburg, Germany; Department of Neurology and Department of Clinical Genomics, Mayo Clinic Florida, Jacksonville, FL, USA), Kathrin Brockmann (Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, and German Center for Neurodegenerative Diseases [DZNE], Tubingen, Germany), Maximilian Hanussek (High Performance and Cloud Computing Group, IT Center (ZDV), University of Tübingen, Tübingen, Germany), Milena Radivojkov-Blagojevic, Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany), Peter Lichtner (Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany).

**Greece:** Athina Maria Simitsi (Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; 1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece), Christos Koros (1st Department of Neurology, Egition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece), Efthimos Dardiotis (Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece), Georges M Hadjigeorgiou (Department of Neurology, Medical School, University of Cyprus, Nicosia, Cyprus), and Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece), Geogia Xiromerisiou (Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece), Leonidas Stefanis (Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; 1st Department of Neurology, Egition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece), Marina Bozi (2nd Department of Neurology, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece), Matina Maniati (Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece).

**Italy:** Anna Zecchinelli (Parkinson Institute, Azienda Socio Sanitaria Territoriale [ASST] Gaetano Pini/CTO, Milano), Enza Maria Valente (Department of Molecular Medicine, University of Pavia, Pavia, and Neurogenetics Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS] Mondino Foundation, Pavia, Italy), Carlo Ferrarese (Department of Neurology, San Gerardo
Hospital, Milan, Center for Neuroscience, University of
Milano Bicocca, Monza, Italy), Francesca Del Sorbo
(Parkinson Institute, Azienda Socio Sanitaria Territoriale
[ASST] Gaetano Pini/CTO, Milano), Gianni Pezzoli
(Parkinson Institute, Azienda Socio Sanitaria Territoriale
[ASST] Gaetano Pini/CTO, Milano), Giorgio Sacilotto
(Parkinson Institute, Azienda Socio Sanitaria Territoriale
[ASST] Gaetano Pini/CTO, Milano), Grazia Annesi
(Institute For Biomedical Research and Innovation,
National Research Council, Cosenza), Laura Brighina
(Department of Neurology, San Gerardo Hospital, Milan,
Center for Neuroscience, Monza, Italy), Letizia Straniero
(Department of Biomedical Sciences, Humanitas Univer-
sity, Milan, Italy), Margherita Canesi (Parkinson Institute,
Azienda Socio Sanitaria Territoriale [ASST] Gaetano Pini/
CTO), Milano, Monica Gagliardi (Institute of Molecular
Bioimaging and Physiology, National Research Council,
Catanzaro), Michela Zina (Parkinson Institute, Azienda
Socio Sanitaria Territoriale (ASST) Gaetano Pini/CTO,
Milano), Micol Avenali (Department of Brain and Behav-
ioural Sciences, University of Pavia, and Istituto di
Ricovero e Cura a Carattere Scientifico [IRCCS] Mondino
Foundation, Pavia, Italy), Nicoletta Meucci (Parkinson
Institute, Azienda Socio Sanitaria Territoriale [ASST]
Gaetano Pini/CTO, Milano), Radha Procopio (Institute of
Molecular Bioimaging and Physiology National Research
Council), Roberto Cilia (Parkinson Institute, Azienda
Socio Sanitaria Territoriale [ASST] Gaetano Pini/CTO,
Milano), Rosanna Asselta (Department of Biomedical Sci-
ences, Humanitas University, Milan, Italy; Humanitas
Clinical and Research Center, IRCCS, Milan, Italy),
Simona Petrucci (Department of Clinical and Molecular
Medicine, Sapienza University of Rome, and UOC Medi-
cal Genetics and Advanced Cell Diagnostics, S. Andrea
University Hospital, Rome, Italy), Stefano Duga
(Department of Biomedical Sciences, Humanitas Univer-
sity, Milan, Italy; Humanitas Clinical and Research Cen-
ter, IRCCS, Milan, Italy).

Japan: Aya Ikeda (Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan), Hirotaka Matsuo (Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Saitama, Japan), Hiroyo Yoshino (Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan, Nobutaka Hattori (Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan), Manabu Fanayama (Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan), Takashi Matsushima (Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan), Yuanzhe Li (Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan), Yusuke Kawamura

(Department of Integrative Physiology and Bio-Nano Med-
icine, National Defense Medical College, Saitama, Japan),
Kenya Nishioka (Department of Neurology, Juntendo Uni-
versity School of Medicine, Bunkyo-ku, Tokyo, Japan).

Korea: Sun Ju Chung (Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea), Yun Joong Kim (Department of Neurology, Yongin Severance Hospital, Yonsei University College of Medicine, South Korea).

Luxembourg: Pierra Kilber (Neurology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg), Zied Landoulsi (Luxembourg Centre for Systems Bio-medicine, Esch-sur-Alzette, Luxembourg).

Netherlands: Bart PC van de Warrenburg (Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands), Bastiaan R Bloem (Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands).

Norway: Jan Aasly (Department of Neurology, St Olav's Hospital and Norwegian University of Science and Technology, Trondheim), Lasse Pihlstrøm (Department of Neurology, Oslo University Hospital, Oslo, Norway), Mathias Toft (Department of Neurology, Oslo University Hospital, Oslo, Norway).

Portugal: Joaquim J Ferreira (Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Department of Neurosciences and Mental Health, Neurology, Hospital de Santa Maria, Centro Hospitalar Universitario Lisboa Norte (CHULN), Lisbon, Portugal), Leonor Correia Guedes (Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Department of Neurosciences and Mental Health, Neurology, Hospital de Santa Maria, Centro Hospitalar Universitario Lisboa Norte (CHULN), Lisbon, Portugal).

Russia: Sophia N Pchelina (Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», St. Petersburg, 188,300, Russia; Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia; Institute of Experimental Medicine, St. Petersburg, Russia).

South Africa: Jonathan Carr (Division of Neurology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa), Soraya Bardien (Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa).

Spain: Eduardo Tolosa (Parkinson and Movement Disorders Unit, Neurology Service, Hospital Clinic, Department of Neurology, Universitat de Barcelona and Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas [CIBERNED], Instituto
de Salud Carlos III, Barcelona), Mario Ezquerra (Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Institut de Neurociències, Universitat de Barcelona, Barcelona, Catalonia), Monica Diez-Fairen (Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain; Movement Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain), Pau Pastor (Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain; Movement Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain), Rubén Fernández-Santiago (Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Institut de Neurociències, Universitat de Barcelona, Barcelona, Catalonia).

**Sweden:** Andrea C. Belin (Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden), Andrea Puschmann (Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Neurology, Lund, Sweden), Clara Hellberg (Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Neurology, Lund, Sweden), Caroline Ran (Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden), Karin Wirdefeldt (Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden), Nancy L Pederson (Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm).

**UK:** Carl E Clarke (University of Birmingham and Sandwell and West Birmingham Hospitals NHS Trust, United Kingdom), Huw R Morris (Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK), Karen E Morrison (Faculty of Medicine, Health and Life Sciences, Queens University, Belfast, United Kingdom), Manuela Tan (Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada), Nicholas Wood (University College London (UCL) Genetics Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom).

**United States:** Dena G Hernandez (Molecular Genetics Section, Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD), Dimitri Krainc (Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL), Connor Edsall (Molecular Genetics

Section, Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD), Lena F. Burbulla (Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL), Matt J. Farrer (Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada), Andy Singleton (Molecular Genetics Section, Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD).

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## Supporting Data

Additional Supporting Information may be found in the online version of this article at the publisher's web-site.