Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.
22 - ?
MetadataShow full item record
BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies.
AuthorsJansen, IE; Ye, H; Heetveld, S; Lechler, MC; Michels, H; Seinstra, RI; Lubbe, SJ; Drouet, V; Lesage, S; Majounie, E; Gibbs, JR; Nalls, MA; Ryten, M; Botia, JA; Vandrovcova, J; Simon-Sanchez, J; Castillo-Lizardo, M; Rizzu, P; Blauwendraat, C; Chouhan, AK; Li, Y; Yogi, P; Amin, N; van Duijn, CM; International Parkinson’s Disease Genetics Consortium (IPGDC); Morris, HR; Brice, A; Singleton, AB; David, DC; Nollen, EA; Jain, S; Shulman, JM; Heutink, P
- College Publications 
Showing items related by title, author, creator and subject.
Hasan, H; Athauda, DS; Foltynie, T; Noyce, AJ (IOS Press, 2017-02-07)Background: The MDS-UPDRS (Movement Disorders Society – Unified Parkinson’s Disease Rating Scale) is the most widely used scale for rating impairment in PD. Subscores measuring bradykinesia have low reliability that can ...
Assessing cognitive dysfunction in Parkinson’s: An online tool to detect visuo-perceptual deficits NOYCE, AJ (Wiley, 2018-02-23)Background: People with Parkinson’s disease (PD) who develop visuo-perceptual deficits are at higher risk of dementia, but we lack tests that detect subtle visuoperceptual deficits and can be performed by untrained ...
What are people with Parkinson's disease really impaired on when it comes to making decisions? A meta-analysis of the evidence. Ryterska, A; Jahanshahi, M; Osman, M (2013-12)Parkinson's disease (PD) is associated with motor and cognitive impairment caused by dopamine dysregulation in the basal ganglia. Amongst a host of cognitive deficits, evidence suggests that decision-making is impaired in ...