Parkinson’s families project: a UK-wide study of early onset and familial Parkinson’s disease
Authors: Towns Clodagh , Fang Zih-Hua , Tan Manuela M. X. , Jasaityte Simona , Schmaderer Theresa M. , Stafford Eleanor J. , Pollard Miriam , Tilney Russel , Hodgson Megan , Wu Lesley , Labrum Robyn , Hehir Jason , Polke James , Lange Lara M. , Schapira Anthony H. V. , Bhatia Kailash P. ,   Parkinson’s Families Project (PFP) Study Group, Morris Huw R. , Real Raquel , Jarman Paul R. , Wood Nicholas W. , Jasaityte Simona , Hodgson Megan , Towns Clodagh , Pollard Miriam , Wakeman Elizabeth , Saifee Tabish , Arianayagam Sam , Shaik Saifuddin , Molloy Sophie , Gregory Ralph , Wickremaratchi Mirdhu , Buccoliero Rosaria , Bandmann Oliver , Paviour Dominic , Padiachy Diran , Misbahuddin Anjum , Cosgrove Jeremy , Guptha Sunku , Chaudhuri Ray , Tai Yen , Asad Sukaina , Funaki Ayano , Kunc Marek , Brierley Charlotte , Sheridan Ray , Truscott Rena , Dean Suzanne , Vickers Carinna , Sophia Rani , Jones Sion , Capps Erica , Archibald Neil , Wiblin Louise , Slaght Sean J. , Jones Edward , Barnes Colin , D’Costa Dominick , Mann Carl , Nath Uma , Schrag Anette , Williams Sarah , Webster Gillian , Sveinbjornsdottir Sigurlaug , Strens Lucy , Hand Annette , Walker Richard , Crouch Rosemary , Raw Jason , Tuck Stephanie , Amar Khaled , Wales Emma , Gentilini Irene , Nacorda Aileen , Hartley Louise ,   Global Parkinson’s Genetics Program (GP2), Singleton Andrew B. , Blauwendraat Cornelis , Klein Christine , Houlden Henry , Wood Nicholas W. , Jarman Paul R. , Morris Huw R. , Real Raquel 
Published: October 2024

AbstractThe 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.