Elucidating causative gene variants in hereditary Parkinson's disease in the Global Parkinson's Genetics Program (GP2)

Lara M Lange¹, Micol Avenali^{2

3}, Melina Ellis^{4

5}, Anastasia Illarionova⁶, Ignacio J Keller Sarmiento⁷, Ai-Huey Tan⁸, Harutyun Madoev¹, Caterina Galandra^{2

9}, Johanna Junker¹, Karisha Roopnarain¹, Justin Solle¹⁰, Claire Wegel¹¹, Zih-Hua Fang⁶, Peter Heutink⁶, Kishore R Kumar^{12

13}, Shen-Yang Lim⁸, Enza Maria Valente^{2

9}, Mike Nalls^{14

15

16}, Cornelis Blauwendraat^{15

17}, Andrew Singleton^{15

16}, Niccolo Mencacci⁷, Katja Lohmann¹, Christine Klein¹⁸; Global Parkinson’s Genetic Program (GP2)

Affiliations

¹ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
² IRCCS Mondino Foundation, Pavia, Italy.
³ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
⁴ Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW, Australia.
⁵ Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
⁶ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁷ Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁸ Division of Neurology, Department of Medicine, and the Mah Pooi Soo and Tan Chin Nam Centre for Parkinson's and Related Disorders, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁹ Department of Molecular Medicine, University of Pavia, Pavia, Italy.
¹⁰ Department of Clinical Research, Michael J. Fox Foundation for Parkinson's Research, New York City, NY, USA.
¹¹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
¹² Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
¹³ Molecular Medicine Laboratory and Neurology Department, Concord Repatriation General Hospital, The University of Sydney, Concord, NSW, Australia.
¹⁴ Data Tecnica International, Washington, DC, USA.
¹⁵ Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
¹⁶ Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
¹⁷ Integrative Genomics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
¹⁸ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. christine.klein@neuro.uni-luebeck.de.

PMID: 37369645
PMCID: PMC10300084
DOI: 10.1038/s41531-023-00526-9

Elucidating causative gene variants in hereditary Parkinson's disease in the Global Parkinson's Genetics Program (GP2)

Lara M Lange et al. NPJ Parkinsons Dis. 2023.

. 2023 Jun 27;9(1):100.

doi: 10.1038/s41531-023-00526-9.

Authors

Affiliations

¹ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
² IRCCS Mondino Foundation, Pavia, Italy.
³ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
⁴ Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW, Australia.
⁵ Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
⁶ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁷ Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁸ Division of Neurology, Department of Medicine, and the Mah Pooi Soo and Tan Chin Nam Centre for Parkinson's and Related Disorders, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁹ Department of Molecular Medicine, University of Pavia, Pavia, Italy.
¹⁰ Department of Clinical Research, Michael J. Fox Foundation for Parkinson's Research, New York City, NY, USA.
¹¹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
¹² Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
¹³ Molecular Medicine Laboratory and Neurology Department, Concord Repatriation General Hospital, The University of Sydney, Concord, NSW, Australia.
¹⁴ Data Tecnica International, Washington, DC, USA.
¹⁵ Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
¹⁶ Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
¹⁷ Integrative Genomics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
¹⁸ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. christine.klein@neuro.uni-luebeck.de.

PMID: 37369645
PMCID: PMC10300084
DOI: 10.1038/s41531-023-00526-9

Erratum in

Author Correction: Elucidating causative gene variants in hereditary Parkinson's disease in the Global Parkinson's Genetics Program (GP2).
Lange LM, Avenali M, Ellis M, Illarionova A, Keller Sarmiento IJ, Tan AH, Madoev H, Galandra C, Junker J, Roopnarain K, Solle J, Wegel C, Fang ZH, Heutink P, Kumar KR, Lim SY, Valente EM, Nalls M, Blauwendraat C, Singleton A, Mencacci N, Lohmann K, Klein C; Global Parkinson’s Genetic Program (GP2). Lange LM, et al. NPJ Parkinsons Dis. 2023 Sep 13;9(1):133. doi: 10.1038/s41531-023-00560-7. NPJ Parkinsons Dis. 2023. PMID: 37704671 Free PMC article. No abstract available.

Abstract

The Monogenic Network of the Global Parkinson's Genetics Program (GP2) aims to create an efficient infrastructure to accelerate the identification of novel genetic causes of Parkinson's disease (PD) and to improve our understanding of already identified genetic causes, such as reduced penetrance and variable clinical expressivity of known disease-causing variants. We aim to perform short- and long-read whole-genome sequencing for up to 10,000 patients with parkinsonism. Important features of this project are global involvement and focusing on historically underrepresented populations.

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Conflict of interest statement

C.K. has received grant support from the Michael J. Fox Foundation for Parkinson’s Research and the Aligning Science Across Parkinson’s Initiative. She serves as a medical advisor to Centogene and Retromer Therapeutics and has received a speaker’s honorarium from Desitin Pharma. S.-Y.L. received grants from the Michael J. Fox Foundation and the Malaysian Ministry of Education Fundamental Research Grant Scheme. A.S. and C.B. have received grant support from the Michael J. Fox Foundation for Parkinson’s Research and the Aligning Science Across Parkinson’s Initiative. A.S. has received royalty payments related to a diagnostic for stroke. M.N. is a consultant employed by Data Tecnica International. Data Tecnica is engaged in a consulting agreement with the US National Institutes of Health. A.S. and K.L. are editors for npj Parkinson’s Disease. A.S. and K.L. were not involved in the journal’s review of, or decisions related to, this manuscript. L.M.L., M.A., M.E., Z.-H.F., C.G., P.H., A.I., J.J., I.J.K.S., K.R.K., H.M., N.M., K.R., A.-H.T., E.M.V., J.S., and C.W. declare no competing interests.

Figures

**Fig. 1. Workflow of the GP2 Monogenic Network.**
Figure 1 displays the general workflow of GP2’s Monogenic Network (a) and the specific data generation and processing workflow (b). a There are four steps: (I) The application process, where interested collaborators register to the Monogenic Portal, ethics documents are reviewed, and the required paperwork is executed. (II) The data and sample sharing, where collaborators ship their samples to GP2’s Monogenic Network and share the respective clinical data for these patients by filling out the eCRFs in the Portal. (III) The genetic analyses that are performed by GP2’s Monogenic Network, in particular, NBA genotyping for all patients and both NBA and WGS for a subset of unsolved, apparently monogenic cases (for details, see b). (IV) The data analyses where generated data are interpreted, and results validated. b All samples from recruited cases will be genotyped with the Illumina NeuroBooster Array. Prioritized samples with an unsolved genetic cause will be whole-genome sequenced (WGS). Additionally, a subset of samples still unsolved after short-read WGS will undergo long-read sequencing. eCRF electronic case report form, GP2 Global Parkinson’s Genetics Program, GWAS genome-wide association studies, NBA NeuroBooster Array, PD Parkinson’s disease, WGS whole-genome sequencing.

**Fig. 2. Outreach of the Monogenic Network (world map) and selected cohort for the 500-genomes pilot project (September 2022).**
Highlighted in blue are countries where potential collaborators have been contacted, and highlighted in green are the countries from which research teams have been involved in the 500-genomes pilot project. Over 60 of these teams from almost 40 countries are already participating in the GP2 project.

See this image and copyright information in PMC

References

1. The Global Parkinson’s Genetics Program (GP2). GP2: The Global Parkinson’s Genetics Program. Mov. Disord. 2021;36:842–851. doi: 10.1002/mds.28494. - DOI - PMC - PubMed
1. Iwaki H, et al. Penetrance of Parkinson’s disease in LRRK2 p.G2019S carriers is modified by a polygenic risk score. Mov. Disord. 2020;35:774–780. doi: 10.1002/mds.27974. - DOI - PMC - PubMed
1. Klein C, Hattori N, Marras C. MDSGene: closing data gaps in genotype-phenotype correlations of monogenic Parkinson’s disease. J. Parkinsons Dis. 2018;8:25–30. doi: 10.3233/JPD-181505. - DOI - PMC - PubMed
1. Trinh J, et al. Utility and implications of exome sequencing in early-onset Parkinson’s disease. Mov. Disord. 2019;34:133–137. doi: 10.1002/mds.27559. - DOI - PMC - PubMed
1. Schumacher-Schuh AF, et al. Underrepresented populations in parkinson’s genetics research: current landscape and future directions. Mov. Disord. 2022;37:1593–1604. doi: 10.1002/mds.29126. - DOI - PMC - PubMed

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Elucidating causative gene variants in hereditary Parkinson's disease in the Global Parkinson's Genetics Program (GP2)

Affiliations

Elucidating causative gene variants in hereditary Parkinson's disease in the Global Parkinson's Genetics Program (GP2)

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources