Parkinson’s families project: a UK-wide study of early onset and familial Parkinson’s disease

Abstract

The Parkinson’s Families Project is a UK-wide study aimed at identifying genetic variation associated with familial and early-onset Parkinson’s disease (PD). We recruited individuals with a clinical diagnosis of PD and age at motor symptom onset ≤45 years and/or a family history of PD in up to third-degree relatives. Where possible, we also recruited affected and unaffected relatives. We analysed DNA samples with a combination of single nucleotide polymorphism (SNP) array genotyping, multiplex ligation-dependent probe amplification (MLPA), and whole-genome sequencing (WGS). We investigated the association between identified pathogenic mutations and demographic and clinical factors such as age at motor symptom onset, family history, motor symptoms (MDS-UPDRS) and cognitive performance (MoCA). We performed baseline genetic analysis in 718 families, of which 205 had sporadic early-onset PD (sEOPD), 113 had familial early-onset PD (fEOPD), and 400 had late-onset familial PD (fLOPD). 69 (9.6%) of these families carried pathogenic variants in known monogenic PD-related genes. The rate of a molecular diagnosis increased to 28.1% in PD with motor onset ≤35 years. We identified pathogenic variants in LRRK2 in 4.2% of families, and biallelic pathogenic variants in PRKN in 3.6% of families. We also identified two families with SNCA duplications and three families with a pathogenic repeat expansion in ATXN2, as well as single families with pathogenic variants in VCP, PINK1, PNPLA6, PLA2G6, SPG7, GCH1, and RAB32. An additional 73 (10.2%) families were carriers of at least one pathogenic or risk GBA1 variant. Most early-onset and familial PD cases do not have a known genetic cause, indicating that there are likely to be further monogenic causes for PD.

Metadata

Item Type:	Article
Authors/Creators:	Towns, C. https://orcid.org/0000-0001-8418-6241 Fang, Z.-H. https://orcid.org/0000-0002-0225-8772 Tan, M.M.X. https://orcid.org/0000-0001-5835-669X Jasaityte, S. https://orcid.org/0009-0009-6030-2901 Schmaderer, T.M. Stafford, E.J. https://orcid.org/0000-0003-2451-4308 Pollard, M. Tilney, R. https://orcid.org/0000-0003-3498-6990 Hodgson, M. Wu, L. https://orcid.org/0000-0001-5464-5603 Labrum, R. Hehir, J. https://orcid.org/0000-0002-8185-9241 Polke, J. Lange, L.M. https://orcid.org/0000-0002-7162-9821 Schapira, A.H.V. https://orcid.org/0000-0002-3018-3966 Bhatia, K.P. https://orcid.org/0000-0001-8185-286X Morris, H.R. Real, R. Jarman, P.R. Wood, N.W. Jasaityte, S. Hodgson, M. Towns, C. Pollard, M. Wakeman, E. Saifee, T. Arianayagam, S. Shaik, S. Molloy, S. Gregory, R. Wickremaratchi, M. Buccoliero, R. Bandmann, O. https://orcid.org/0000-0003-3149-0252 Paviour, D. Padiachy, D. Misbahuddin, A. Cosgrove, J. Guptha, S. Chaudhuri, R. Tai, Y. Asad, S. Funaki, A. Kunc, M. Brierley, C. Sheridan, R. Truscott, R. Dean, S. Vickers, C. Sophia, R. Jones, S. Capps, E. Archibald, N. Wiblin, L. Slaght, S.J. Jones, E. Barnes, C. D’Costa, D. Mann, C. Nath, U. Schrag, A. Williams, S. Webster, G. Sveinbjornsdottir, S. Strens, L. Hand, A. Walker, R. Crouch, R. Raw, J. Tuck, S. Amar, K. Wales, E. Gentilini, I. Nacorda, A. Hartley, L. Singleton, A.B. https://orcid.org/0000-0001-5606-700X Blauwendraat, C. https://orcid.org/0000-0001-9358-8111 Klein, C. https://orcid.org/0000-0003-2102-3431 Houlden, H. https://orcid.org/0000-0002-2866-7777 Wood, N.W. https://orcid.org/0000-0002-9500-3348 Jarman, P.R. Morris, H.R. https://orcid.org/0000-0002-5473-3774 Real, R. https://orcid.org/0000-0001-8117-742X
Copyright, Publisher and Additional Information:	© 2024 The Authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Parkinson’s Families Project (PFP) Study Group; Global Parkinson’s Genetics Program (GP2)
Dates:	Published: 17 October 2024 Published (online): 17 October 2024 Accepted: 12 August 2024
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Depositing User:	Symplectic Sheffield
Date Deposited:	12 Nov 2024 11:49
Last Modified:	12 Nov 2024 11:49
Published Version:	http://dx.doi.org/10.1038/s41531-024-00778-z
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41531-024-00778-z
Related URLs:	PubMed URL Dataset Dataset Dataset Software or Code Software or Code Software or Code Software or Code Software or Code
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:219546

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Parkinson’s families project: a UK-wide study of early onset and familial Parkinson’s disease

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Parkinson’s families project: a UK-wide study of early onset and familial Parkinson’s disease

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