Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing

Iris E. Jansen, Hui Ye, Sasja Heetveld, Marie C. Lechler, Helen Michels, Renée I. Seinstra, Steven J. Lubbe, Valérie Drouet, Suzanne Lesage, Elisa Majounie, J. Raphael Gibbs, Mike A. Nalls, Mina Ryten, Juan A. Botia, Jana Vandrovcova, Javier Simon-Sanchez, Melissa Castillo-Lizardo, Patrizia Rizzu, Cornelis Blauwendraat, Amit K. ChouhanYarong Li, Puja Yogi, Najaf Amin, Cornelia M. van Duijn, International Parkinson's Disease Genetics Consortium (IPGDC), Huw R. Morris, Alexis Brice, Della C. David, Andrew B. Singleton, Ellen A. Nollen, Shushant Jain, Joshua M. Shulman, Peter Heutink, David J. Burn, Robert Walker, Karen Morrison

Research output: Contribution to journalArticlepeer-review

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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.
Original languageEnglish
Pages (from-to)1-26
Number of pages26
JournalGenome Biology
Issue number22
Publication statusPublished - 30 Jan 2017


  • Animal model
  • Functional screening
  • Genomics
  • Loss-of-function
  • Mitochondria
  • Parkin
  • Parkinson's disease
  • Rare variants
  • Whole-exome sequencing
  • α-synuclein

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