Parkinson’s Families Project: a UK-wide study of early onset and familial Parkinson’s disease

Abstract

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. 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 completed baseline genetic analysis in 714 families, of which 196 had sporadic early-onset PD (sEOPD), 112 had familial early-onset PD (fEOPD) and 406 had late-onset familial PD (fLOPD). 53 (7.4%) of these families carried known pathogenic variants causing PD. We identified pathogenic mutations inLRRK2in 4.1% of families, and bi-allelic pathogenic mutations inPRKNin 2.4% of families. We also identified pathogenic mutations in two families withSNCAduplications, and single families with pathogenic mutations inVCP,PINK1,PNPLA6,PLA2G6andSPG7. 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.