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

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

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.

Animal model, Functional screening, Genomics, Loss-of-function, Mitochondria, Parkin, Parkinson's disease, Rare variants, Whole-exome sequencing, α-synuclein
1474-7596
1-26
Jansen, Iris E.
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Ye, Hui
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Heetveld, Sasja
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Lechler, Marie C.
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Michels, Helen
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Seinstra, Renée I.
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Lubbe, Steven J.
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Drouet, Valérie
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Lesage, Suzanne
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Majounie, Elisa
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Gibbs, J. Raphael
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Nalls, Mike A.
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Ryten, Mina
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Botia, Juan A.
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Vandrovcova, Jana
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Simon-Sanchez, Javier
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Castillo-Lizardo, Melissa
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Rizzu, Patrizia
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Blauwendraat, Cornelis
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Chouhan, Amit K.
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Li, Yarong
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Yogi, Puja
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Amin, Najaf
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van Duijn, Cornelia M.
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Morris, Huw R.
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Brice, Alexis
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David, Della C.
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Singleton, Andrew B.
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Nollen, Ellen A.
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Jain, Shushant
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Shulman, Joshua M.
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Heutink, Peter
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Burn, David J.
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Walker, Robert
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Morrison, Karen
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International Parkinson's Disease Genetics Consortium (IPGDC)
Jansen, Iris E.
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Ye, Hui
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Heetveld, Sasja
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Lechler, Marie C.
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Michels, Helen
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Seinstra, Renée I.
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Lubbe, Steven J.
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Drouet, Valérie
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Lesage, Suzanne
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Majounie, Elisa
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Gibbs, J. Raphael
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Nalls, Mike A.
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Ryten, Mina
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Botia, Juan A.
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Vandrovcova, Jana
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Simon-Sanchez, Javier
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Castillo-Lizardo, Melissa
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Rizzu, Patrizia
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Blauwendraat, Cornelis
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Chouhan, Amit K.
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Li, Yarong
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Yogi, Puja
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Amin, Najaf
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van Duijn, Cornelia M.
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Morris, Huw R.
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Brice, Alexis
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David, Della C.
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Singleton, Andrew B.
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Nollen, Ellen A.
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Jain, Shushant
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Shulman, Joshua M.
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Heutink, Peter
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Burn, David J.
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Walker, Robert
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Morrison, Karen
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Jansen, Iris E., Ye, Hui, Heetveld, Sasja, Lechler, Marie C., Michels, Helen, Seinstra, Renée I., Lubbe, Steven J., Drouet, Valérie, Lesage, Suzanne, Majounie, Elisa, Gibbs, J. Raphael, Nalls, Mike A., Ryten, Mina, Botia, Juan A., Vandrovcova, Jana, Simon-Sanchez, Javier, Castillo-Lizardo, Melissa, Rizzu, Patrizia, Blauwendraat, Cornelis, Chouhan, Amit K., Li, Yarong, Yogi, Puja, Amin, Najaf, van Duijn, Cornelia M., Morris, Huw R., Brice, Alexis, David, Della C., Singleton, Andrew B., Nollen, Ellen A., Jain, Shushant, Shulman, Joshua M. and Heutink, Peter , International Parkinson's Disease Genetics Consortium (IPGDC) (2017) Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing. Genome Biology, 18 (22), 1-26, [22]. (doi:10.1186/s13059-017-1147-9).

Record type: Article

Abstract

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.

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s13059-017-1147-9 - Version of Record
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Accepted/In Press date: 3 January 2017
e-pub ahead of print date: 30 January 2017
Keywords: Animal model, Functional screening, Genomics, Loss-of-function, Mitochondria, Parkin, Parkinson's disease, Rare variants, Whole-exome sequencing, α-synuclein

Identifiers

Local EPrints ID: 417055
URI: http://eprints.soton.ac.uk/id/eprint/417055
ISSN: 1474-7596
PURE UUID: ea1e4982-efe3-4e41-b49d-a583ddd04da4
ORCID for Karen Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 18 Jan 2018 17:30
Last modified: 18 Feb 2021 17:26

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Contributors

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

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