ArticleGenome biology2017
Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.
Article in Genome biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers, 2 of them syntheses that pooled it.
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Who cites it
72 citing papers in PubMed, 2 syntheses or guidelines pooled it, 121 citations in OpenAlex.
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- Case Report: Decoding genetic risks of vascular parkinsonism: a case series.Frontiers in genetics · 2025Article
- Biogenesis of Rab14-positive Endosome Buds at Golgi-endosome Contacts by the RhoBTB3-SHIP164-Vps26B Complex.Current medical science · 2024Article
- VPS13C regulates phospho-Rab10-mediated lysosomal function in human dopaminergic neurons.The Journal of cell biology · 2024Article
- Biogenesis of Rab14-positive endosome buds at Golgi-endosome contacts by the RhoBTB3-SHIP164-Vps26B complex.Cell discovery · 2024Article
- Deep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies.bioRxiv : the preprint server for biology · 2024Article
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- Differential methylation analysis in neuropathologically confirmed dementia with Lewy bodies.Communications biology · 2024Article
- Circular RNA hsa_circ_0005939 Regulates UHRF1BP1L Expression by Targeting miR-4693-3p to Promote Colorectal Cancer Progression.Protein and peptide letters · 2024Article
- Genome-wide association and replication studies for handedness in a Korean community-based cohort.Brain and behavior · 2023Article
- Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity.PLoS genetics · 2023Article
- The systematic comparison between Gaussian mirror and Model-X knockoff models.Scientific reports · 2023Article
12 more citing papers are in PubMed but not listed here.
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Authors and funding
33 authors at 14 institutions in 5 countries.
Funding
Abstract
backgroundWhole-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.
resultsAssuming 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.
conclusionsBy 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.
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