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

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.

Authors

Institutions

Publication Details

Journal
npj Parkinson s Disease
Published
2024-10-17
DOI
https://doi.org/10.1038/s41531-024-00778-z
Citations
21
Primary Topic
Parkinson's Disease Mechanisms and Treatments
Type
article
Field-Weighted Citation Impact
7.75

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Anjum Misbahuddin, Raquel Real, Rosaria Buccoliero, Yen Tai et al.
21 citations
npj Parkinson s Disease
Parkinson's Disease Mechanisms and Treatments
7.75
article

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

Anjum Misbahuddin, Raquel Real, Rosaria Buccoliero, Yen Tai, Rosemary Crouch, Ray Sheridan, Ralph Gregory, Lesley Wu, R. B. Truscott, Megan Hodgson, Ayano Funaki, Annette Hand, Russel Tilney, Zih‐Hua Fang, Sigurlaug Sveinbjörnsdóttir, Charlotte Brierley, Christine Klein, Erica Capps, Khaled Amar, К. Ray Chaudhuri, Louise Wiblin, Sophie Molloy, Sukaina Asad, Jason Raw, Clodagh Towns, Jeremy Cosgrove, Manuela Tan, Lara Mariah Lange, Carl Mann, Colin Barnes, Sean Slaght, Carinna Vickers, Suzanne Dean, Anthony H.V. Schapira, Louise Hartley, Eleanor J. Stafford, Nicholas William Wood, Diran Padiachy, Anette E. Schrag, Cornelis Blauwendraat, Rani Sophia, Dominic Paviour, Marek Kunc, Henry Houlden, Robyn Labrum, Edward L. Jones, Mirdhu Wickremaratchi, Tabish A. Saifee, I. Gentilini, Andrew B. Singleton, Jason Hehir, Kailash P. Bhatia, Sion Jones, Uma Nath, Theresa M. Schmaderer, Simona Jasaityte, James Polke, Sunku H. Guptha, Oliver Bandmann, Gillian Webster, E Wales, D F D'Costa, S. M. Tuck, Richard Walker, Neil Archibald, Paul Jarman, Sarah Williams, Miriam Pollard, Saifuddin Shaik, Lucy Strens, Elizabeth Wakeman, Sam Arianayagam, Aileen Nacorda
article en
21 citations

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.

npj Parkinson s DiseaseVol. 10(1)
Oslo University Hospital (NO), Betsi Cadwaladr University Health Board (GB), Barking, Havering And Redbridge University Hospitals NHS Trust (GB), Lancashire Teaching Hospitals NHS Foundation Trust (GB), National Institutes of Health (US), Imperial College Healthcare NHS Trust (GB), Queen Mary University of London (GB), King's College London (GB), Barts Health NHS Trust (GB), University of Cambridge (GB), Leeds Teaching Hospitals NHS Trust (GB), Royal Devon & Exeter NHS Foundation Trust (GB), Royal Cornwall Hospital Trust (GB), North Tyneside General Hospital (GB), Royal Cornwall Hospital (GB), New Cross Hospital (GB), Hillingdon Hospitals NHS Foundation Trust (GB), West Suffolk NHS Foundation Trust (GB), Fairfield General Hospital (GB), University Hospitals of North Midlands NHS Trust (GB), Yeovil District Hospital NHS Foundation Trust (GB), Peterborough City Hospital (GB), Luton and Dunstable University Hospital NHS Foundation Trust (GB), Royal Stoke University Hospital (GB), Birmingham Community Healthcare NHS Trust (GB), London North West Healthcare NHS Trust (GB), Worthing Hospital (GB), Solent NHS Trust (GB), St Helens and Knowsley Teaching Hospitals NHS Trust (GB), Dorset County Hospital NHS Foundation Trust (GB), Poole Hospital (GB), Northumbria Healthcare NHS Foundation Trust (GB), The Royal Free Hospital (GB), James Cook University Hospital (GB), St George’s University Hospitals NHS Foundation Trust (GB), Royal London Hospital (GB), Scarborough General Hospital (GB), Broomfield Hospital (GB), German Center for Neurodegenerative Diseases (DE), Isle of Wight NHS Trust (GB), Royal Shrewsbury Hospital (GB), University Hospitals of Leicester NHS Trust (GB), Harrogate and District NHS Foundation Trust (GB), Queen Alexandra Hospital (GB), University Hospital Southampton NHS Foundation Trust (GB), South Tees Hospitals NHS Foundation Trust (GB), Airedale NHS Foundation Trust (GB), Hampshire Hospitals NHS Foundation Trust (GB), Northumbria University (GB), North Cumbria Integrated Care NHS Foundation Trust (GB), Central London Community Healthcare NHS Trust (GB), Norfolk Community Health and Care NHS Trust (GB), National Institute of Neurological Disorders and Stroke (US), King's College Hospital NHS Foundation Trust (GB), University Hospital Schleswig-Holstein (DE), Sunderland Royal Hospital (GB), Taunton & Somerset NHS Foundation Trust (GB), Coventry (United Kingdom) (GB), St Mary's Hospital (GB), South Tyneside and Sunderland NHS Foundation Trust (GB), National Institute on Aging (US), UCL Biomedical Research Centre (GB), Wye Valley NHS Trust (GB), Shrewsbury and Telford Hospital NHS Trust (GB), University Hospitals Sussex NHS Foundation Trust (GB), National Hospital for Neurology and Neurosurgery (GB), The Royal Wolverhampton NHS Trust (GB), Research Network (United States) (US), NIHR Research Delivery Network (GB), St. Mary's Hospital (GB), University Hospitals Dorset NHS Foundation Trust, Somerset NHS Foundation Trust, University College London (GB), Imperial College London (GB), Salisbury NHS Foundation Trust (GB), University of Sheffield (GB), University of Lübeck (DE)
Michael J. Fox Foundation for Parkinson's Research, Cure Parkinson’s Trust, Wellcome Trust, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, Parkinson's UK, Medical Research Council
Good health and well-being
Openalex Percentile: Top 2%
Parkinson's Disease Mechanisms and Treatments
7.75
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.