Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

the MJFF Global Genetic Parkinson's Disease Study Group

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)286-303
Number of pages18
JournalMovement Disorders
Volume38
Issue number2
DOIs
StatePublished - 1 Feb 2023

Funding

FundersFunder number
AEGIUM
Bigglesworth Family Foundation
Donald G. and Jodi P. Heeringa Family
Emalex Biosciences, Inc.
EraNet Neuron
FP Pharmaceutical
Haworth Family Professorship in Neurodegenerative Diseases fund
ISCIII‐FEDERPI18/01898
Instituto de Salud Carlos III‐Fondo Europeo de Desarrollo Regional
Karolinska Institutet Research Funds
Luisa Mariani Foundation
MRFF NHMRCAPP2007959, APP11179029, App1136800, APP1184403
Mellby Gård Foundation
Ministry of Research
Parkinson Fonds Deutschland
Parkinson Fonds Deutschland gGmbH
Slovak Grant and Development AgencyAPVV‐18‐0547
ZPM Innovation
ZSE‐DUO
National Institutes of Health1U01NS107016‐01A1
National Institutes of Health
U.S. Department of Defense
National Institute of Neurological Disorders and StrokeR01 NS085070, U54 NS110435
National Institute of Neurological Disorders and Stroke
Congressionally Directed Medical Research ProgramsW81XWH‐17‐1‐0249
Congressionally Directed Medical Research Programs
Michael J. Fox Foundation for Parkinson's Research15015.02
Michael J. Fox Foundation for Parkinson's Research
American Brain Foundation
CHDI Foundation
Teva Pharmaceutical Industries
American Parkinson Disease Association
Fundación Alicia Koplowitz
Japan Agency for Medical Research and Development22kk030517h0001, 17ek0109207h0001
Japan Agency for Medical Research and Development
Horizon 2020 Framework Programme
Parkinson's Foundation
UK Research and Innovation
Dystonia Coalition
Manchester Biomedical Research CentreBRC‐1215‐20014
Manchester Biomedical Research Centre
Revance
European Parkinson’s Disease Association
Aligning Science Across Parkinson’s
Albertson Parkinson's Research Foundation
Medical Research CouncilMR/R007446/1
Medical Research Council
Parkinson's UK
Research Councils UK
Tenovus
European Commission
National Health and Medical Research CouncilAPP1151906
National Health and Medical Research Council
Deutsche ForschungsgemeinschaftRi 682/20‐1, Ri 682/19‐1
Deutsche Forschungsgemeinschaft
Japan Society for the Promotion of Science17H04056, 21H02836, 20K07878, 19K08003
Japan Society for the Promotion of Science
Japan Science and Technology Agency
Bundesministerium für Bildung und Forschung
Fondazione Telethon
Fondazione Cariplo
Consejería de Economía, Innovación, Ciencia y Empleo, Junta de AndalucíaCTS‐7685, CVI‐02526
Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía
Ministero della Salute
Ministry of Education and Science of the Russian Federation
Hjärnfonden
Ministarstvo Prosvete, Nauke i Tehnološkog Razvoja
Ministerio de Ciencia e InnovaciónRTC2019‐007150‐1
Ministerio de Ciencia e Innovación
Russian Science Foundation
European Regional Development FundITMS2014+:313011V455
European Regional Development Fund
Hilde-Ulrichs-Stiftung für Parkinsonforschung
Consejería de Salud y Familias, Junta de AndalucíaPE‐0186‐2019
Consejería de Salud y Familias, Junta de Andalucía
H. Lundbeck A/S
Damp Stiftung
Deutsche Parkinson Vereinigung

    Keywords

    • Parkinson's disease
    • monogenic PD

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