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.

Fig. 1. Parkinson’s families project overview.

Participants are recruited across 43 sites in the UK. Index cases must be ≥18 years, have capacity to consent, have a diagnosis of PD with symptom onset ≤45 and/or family history of PD. All participants donate a blood sample for DNA extraction. Affected participants additionally donate blood for peripheral blood lymphocyte extraction, which are sent to the European Collection of Authenticated Cell Cultures (ECACC) for transformation into lymphoblastoid cell lines and storage. All affected participants fill out a questionnaire with detailed medical and family history, environmental, drug and lifestyle exposures, as well as the following questionnaires: Parkinson’s Disease Questionnaire (PDQ-8), EQ-5D, Epworth Sleepiness Scale (ESS), REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), Panic Disorder Severity Scale (PDSS), Hospital Anxiety and Depression Scale (HADS), Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP), Scales for Outcomes in Parkinson’s disease - Autonomic Dysfunction (SCOPA-AUT), Fecal Incontinence and Constipation Questionnaire (FICQ), MDS-UPDRS parts IB and II. Affected participants recruited on-site are also assessed by an experienced investigator, who rates the MDS-UPDRS parts IA, III and IV, MoCA and Hoehn & Yahr scales. WGS whole-genome sequencing, MLPA multiplex ligation-dependent probe amplification assay, NCA NeuroChip genotyping array.