Abstract
Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials.
| Original language | English |
|---|---|
| Pages (from-to) | 286-303 |
| Number of pages | 18 |
| Journal | Movement disorders : official journal of the Movement Disorder Society |
| Volume | 38 |
| Issue number | 2 |
| Early online date | 24 Jan 2023 |
| DOIs | |
| Publication status | Published - Feb 2023 |
| Externally published | Yes |
Keywords
- monogenic PD
- Parkinson's disease
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In: Movement disorders : official journal of the Movement Disorder Society, Vol. 38, No. 2, 02.2023, p. 286-303.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Embracing Monogenic Parkinson's Disease
T2 - The MJFF Global Genetic PD Cohort
AU - Vollstedt, Eva Juliane
AU - Schaake, Susen
AU - Lohmann, Katja
AU - Padmanabhan, Shalini
AU - Brice, Alexis
AU - Lesage, Suzanne
AU - Tesson, Christelle
AU - Vidailhet, Marie
AU - Wurster, Isabel
AU - Hentati, Faycel
AU - Mirelman, Anat
AU - Giladi, Nir
AU - Marder, Karen
AU - Waters, Cheryl
AU - Fahn, Stanley
AU - Kasten, Meike
AU - Brüggemann, Norbert
AU - Borsche, Max
AU - Foroud, Tatiana
AU - Tolosa, Eduardo
AU - Garrido, Alicia
AU - Annesi, Grazia
AU - Gagliardi, Monica
AU - Bozi, Maria
AU - Stefanis, Leonidas
AU - Ferreira, Joaquim J.
AU - Correia Guedes, Leonor
AU - Avenali, Micol
AU - Petrucci, Simona
AU - Clark, Lorraine
AU - Fedotova, Ekaterina Y.
AU - Abramycheva, Natalya Y.
AU - Alvarez, Victoria
AU - Menéndez-González, Manuel
AU - Jesús Maestre, Silvia
AU - Gómez-Garre, Pilar
AU - Mir, Pablo
AU - Belin, Andrea Carmine
AU - Ran, Caroline
AU - Lin, Chin Hsien
AU - Kuo, Ming Che
AU - Crosiers, David
AU - Wszolek, Zbigniew K.
AU - Ross, Owen A.
AU - Jankovic, Joseph
AU - Nishioka, Kenya
AU - Funayama, Manabu
AU - Clarimon, Jordi
AU - Williams-Gray, Caroline H.
AU - Krüger, Rejko
AU - the MJFF Global Genetic Parkinson's Disease Study Group
AU - Klein, Christine
N1 - Funding Information: Carolyn M. Sue: Intellectual Property Rights: WO 2015/157794 A1. Advisory Boards: AbbVie. Employment: Northern Sydney Local Health District, Sydney, Australia. Honoraria: The International Movement Disorder Society for course directorships and invited lectures. Patents: WO 2015/157794 A1. Grants: 2018–22 NHMRC Partnership grant (APP1151906); 2018–22 MRFF NHMRC Practitioner Fellowship (App1136800); 2020–2025 NHMRC Partnership grant (APP11179029); 2020–2023 NHMRC Ideas Grant (APP1184403); 2021–5 MRFF 2020 Genomics Health Futures Mission Grant (APP2007959); 2021–23 ASAP Project grant Funding Information: Natalya Y. Abramycheva: Employment: Research Center of Neurology, Ministry of Science and Higher Education of the Russian Federation, Moscow, Russia. Grants: Russian Science Foundation Funding Information: Rachel Saunders‐Pullman: Employment: Icahn School of Medicine at Mount Sinai, New York City, New York, USA. Grants: NIH 1U01NS107016‐01A1; Bigglesworth Family Foundation. Others: Bachmann‐Strauss Chair Funding Information: Zbigniew K. Wszolek: Advisory Boards: Vigil Neuroscience, Inc. Employment: Mayo Clinic, Jacksonville, Florida, USA. Grants: NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, PI or co‐PI on Biohaven Pharmaceuticals, Inc. (BHV4157‐206 and BHV3241‐301), Neuraly, Inc. (NLY01‐PD‐1), and Vigil Neuroscience, Inc. (VGL101‐01.001 and VGL101‐01.002). He also serves as the co‐PI of the Mayo Clinic APDA Center for Advanced Research. Others: Donations from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation Funding Information: Vladimir S. Kostic: Employment: School of Medicine, University of Belgrade, Serbia. Grants: Project No 175090 Ministry of Education, Science and Technological Development of Serbia. Project Ф‐28 Serbian Academy of Science and Arts Funding Information: Daniela Berg: Consultancies: Biogen, BIAL, UCB Pharma GmbH, AC Immune SA. Advisory Boards: Biogen, BIAL, UCB Pharma GmbH, AC Immune SA. Employment: Kiel University, Kiel, Germany. Grants: Deutsche Forschungsgemeinschaft (DFG), German Parkinson's Disease Association (dPV), BMBF, Parkinson Fonds Deutschland gGmbH, UCB Pharma GmbH, EU, Novartis Pharma GmbH, Lundbeck, Damp Foundation, The Michael J. Fox Foundation Funding Information: Matej Skorvanek: Consultancies: Medis. Advisory Boards: AbbVie, Stada. Employment: University of P. J. Safarik, Kosice, Slovakia, University Hospital L. Pasteur, Kosice, Slovakia. Contracts: Ministry of Healthcare, Slovakia, Paneuropean University, Bratislava, Slovakia. Honoraria: AbbVie, Boston Scientific, Krka, Medtronic, Stada, UCB. Grants: Operational Programme Integrated Infrastructure, funded by the ERDF [ITMS2014+:313011V455]; Slovak Grant and Development Agency [APVV‐18‐0547] Funding Information: Pablo Mir: Employment: University of Seville, Seville, Spain. Honoraria: Abbott, Allergan, AbbVie, Bial, Britannia, Italfarmaco, Merz, UCB, Teva, and Zambon. Grants: Spanish Ministry of Science and Innovation [RTC2019‐007150‐1], the Instituto de Salud Carlos III‐Fondo Europeo de Desarrollo Regional (ISCIII‐FEDER) [PI18/01898], the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI‐02526, CTS‐7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [PI‐0471‐2013, PE‐0210‐2018, PI‐0459‐2018, PE‐0186‐2019], and the Fundación Alicia Koplowitz Funding Information: George D. Mellick: Employment: Griffith University, Brisbane, Australia. Grants: Australian NHMRC, AEGIUM Foundation Queensland, Griffith University, Philanthropic Donors Funding Information: This project was funded by The Michael J. Fox Foundation (ID 15015.02). Funding agency: Funding Information: Roy N. Alcalay: RNA is funded by the NIH, DoD, the Parkinson's Foundation, and The Michael J. Fox Foundation. Consultancy: Avrobio, Caraway, GSK, Merck, Ono Therapeutics, and Genzyme/Sanofi Funding Information: Manabu Funayama: Employment: Juntendo University, Tokyo, Japan. Grants: (1) JSPS KAKENHI [grant numbers 19K08003 and 20K07878]. Subsidies for Current Expenditures to Private Institutions of Higher Education from the Promotion and Mutual Aid Corporation for Private Schools of Japan. Funding Information: Joseph Jankovic: Consultancies: AbbVie, Aeon BioPharma, Neurocrine, Revance Therapeutics, Teva Pharmaceutical Industries Ltd. Advisory Boards: AbbVie., Teva Pharmaceutical Industries Ltd. Employment: Baylor College of Medicine, Houston, Texas. Honoraria: Movement Disorders Society; Massachusetts General Hospital. Royalties: Cambridge, Elsevier, Medlink Neurology, Lippincott Williams and Wilkins, UpToDate, Wiley‐Blackwell. Grants: AbbVie, CHDI Foundation, Dystonia Coalition, Emalex Biosciences, Inc., Medtronic Neuromodulation, Michael J. Fox Foundation for Parkinson Research, Parkinson's Foundation, Revance Therapeutics, Inc., Teva Pharmaceutical Industries Ltd. Funding Information: Brit Mollenhauer: Consultancies: AbbVie, Servier, and Amprion. Advisory Boards: Roche, Biogen, 4D Pharma PLC. Employment: Paracelsus‐Kliniken Deutschland and University Medical Center, Göttingen, Germany. Contracts: A member of the executive steering committee of the Parkinson Progression Marker Initiative and PI of the Systemic Synuclein Sampling Study of The Michael J. Fox Foundation for Parkinson's Research other than the ones mentioned earlier. Grants: Deutsche Forschungsgemeinschaft (DFG), EU (Horizon2020), Parkinson Fonds Deutschland, Deutsche Parkinson Vereinigung, Parkinson's Foundation, Hilde‐Ulrichs‐Stiftung für Parkinsonforschung, Aligning Science Across Parkinson's (ASAP), and The Michael J. Fox Foundation for Parkinson's Research Funding Information: Esther M. Sammler: Advisory Boards: ABN Neurogenetics working group. Employment: University of Dundee, Dundee, UK. Grants: CSO Senior Clinical Fellowship, MJFF, Tenovus grants Funding Information: Caroline H. Williams‐Gray: Consultancies: Evidera, Inc. Employment: University of Cambridge, UK and Cambridge University Hospitals NHS Trust, Cambridge, UK. Honoraria: GSK. Grants: Cure Parkinson's, Parkinson's UK, The Evelyn Trust, NIHR Biomedical Research Centre (BRC‐1215‐20014), Cambridge Centre for Parkinson‐Plus, RCUK/UKRI Research Innovation, Fellowship awarded by the Medical Research Council (MR/R007446/1) Funding Information: Andrea Carmine Belin: Employment: Karolinska Institutet, Stockholm, Spain. Grants: Swedish Brain Foundation and the Mellby Gård Foundation, Region Stockholm (ALF project), Karolinska Institutet Research Funds Funding Information: Owen A. Ross: Employment: Mayo Clinic, Jacksonville, Florida, USA. Grants: National Institute of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) [R01 NS085070 and U54 NS110435], the Department of Defense Congressionally Directed Medical Research Programs (CDMRP) [W81XWH‐17‐1‐0249], The Michael J. Fox Foundation for Parkinson's Research (MJFF), the American Parkinson Disease Association (APDA), and American Brain Foundation. Funding Information: Nobutaka Hattori: Stock ownership in medically related fields: Equity stock (8%) of PARKINSON Laboratories Co. Ltd., Intellectual Property Rights: Pendint: One PCT/JP2021/034721. Consultancies: Kyowa Kirin, PARKINSON Laboratories Co. Ltd., Dai‐Nippon Sumitomo Pharma, Teijin Pharma Limited, Takeda Pharmaceutical, Biogen Idec Japan. Expert Testimony: Mitsubishi Tanabe Pharma, Medtronic, Inc. Advisory Boards: Dai‐Nippon Sumitomo Pharma, Takeda Pharmaceutical, Kyowa Kirin, Teijin Pharma Limited, Novartis Pharma, Ono Pharmaceutical, AbbVie GK, TOWA PHARMACEUTICAL. Employment: Juntendo University, Tokyo, Japan. Team Leader: Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science. Honoraria: Dai‐Nippon Sumitomo Pharma, Takeda Pharmaceutical, Kyowa Kirin, AbbVie GK, Otsuka Pharmaceutical, Novartis Pharma, Teijin Pharma Limited, Pfizer Japan, Inc., Ono Pharmaceutical, Eisai, Nihon Medi‐physics, Daiichi Sankyo. Grants: Public Research Funds: Japan Society for the Promotion of Science (JSPS), Japan Agency for Medical Research and Development (AMED), Health Labour Sciences Research Grant, Japan Science and Technology Agency(JST). Grants: FP Pharmaceutical. Others: Grants and Endowed Departments and Joint Research Departments: Medtronic, Inc., Boston Scientific, TEIJIN PHARMA, AbbVie GK, FP Pharmaceutical, Dai‐Nippon Sumitomo Pharma, Nihon Medi‐physics, Eisai, Kirin Holdings, Mitsubishi UFJ Trust and Banking Co., GLORY LTD., Otsuka Pharmaceutical, Meiji Seika Pharma, Ono Pharmaceutical, FUJIFILM Wako Pure Chemical, Sunwels, Inc., OHARA Pharmaceutical, PARKINSON Laboratories Co. Ltd, Kyowa Kirin Co., Ltd, Takeda Pharma Co., Ltd, Mitsubishi Tanabe Pharma Funding Information: Olaf Riess: Employment: The University Tübingen, Tübingen, Germany. Grants: SOLVE‐RD (EU), ZSE‐DUO (Innovation grant), ZPM Innovation (Ministry of Research), DFG Ri 682/19‐1, DFG Ri 682/20‐1, DFG NGS‐CCN NCCT Funding Information: Shen‐Yang Lim: Consultancies: The Michael J. Fox Foundation, Lundbeck International Neuroscience Foundation Editorial Board. Advisory Boards: Eisai. Employment: University of Malaya, Kuala Lumpur, Malaysia. Honoraria: International Parkinson and Movement Disorder Society (MDS), International Brain Research Organization (IBRO), Lundbeck, Medtronic. Grants: The Michael J. Fox Foundation, Malaysian Ministry of Education Fundamental Research Grant Scheme Funding Information: Ai Huey Tan: Consultancies: Global Parkinson Genetics Program (GP2). Employment: University of Malaya, Kuala Lumpur, Malaysia. Grants: The Michael J. Fox Foundation; Toray Science Foundation; Malaysia Ministry of Higher Education Fundamental Research Grant Scheme Funding Information: Wataru Satake: Employment: University of Tokyo, Tokyo, Japan. Grants: AMED (grant numbers 17ek0109207h0001 and 22kk030517h0001) and JSPS (under grant numbers 21H02836 and 17H04056). Publisher Copyright: © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
PY - 2023/2
Y1 - 2023/2
N2 - Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials.
AB - Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials.
KW - monogenic PD
KW - Parkinson's disease
UR - http://www.scopus.com/inward/record.url?scp=85147202939&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/36692014
U2 - 10.1002/mds.29288
DO - 10.1002/mds.29288
M3 - Article
C2 - 36692014
SN - 0885-3185
VL - 38
SP - 286
EP - 303
JO - Movement disorders : official journal of the Movement Disorder Society
JF - Movement disorders : official journal of the Movement Disorder Society
IS - 2
ER -