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, Huw R. Morris, Alexis Brice, Andrew B. Singleton, Della C. David, Ellen A. Nollen, Shushant Jain, Joshua M. Shulman*, Peter Heutink, Dena G. Hernandez, Sampath Arepalli, Janet Brooks, Ryan Price, Aude Nicolas, Sean Chong, Mark R. Cookson, Allissa Dillman, Matthew Moore, Bryan J. Traynor, Andrew B. Singleton, Vincent Plagnol, W Wood Nicholas W Wood, Una Marie Sheerin, M Bras Jose M Bras, Gavin Charlesworth, Michelle Gardner, Rita Guerreiro, Daniah Trabzuni, John Hardy, Manu Sharma, Mohamad Saad, Simón-Sánchez Javier Simón-Sánchez, Claudia Schulte, Jean Christophe Corvol, Alexandra Dürr, Marie Vidailhet, Sigurlaug Sveinbjörnsdóttir, Roger Barker, H Williams-Gray Caroline H Williams-Gray, Yoav Ben-Shlomo, Henk W. Berendse, Karin D. van Dijk, Daniela Berg, Kathrin Brockmann, Isabel Wurster, Walter Mätzler, Thomas Gasser, Maria Martinez, Rob M A de Bie, Alessandro Biffi, Daan Velseboer, Bas Bloem, Bart Post, Mirdhu Wickremaratchi, Bart van de Warrenburg, Zoltan Bochdanovits, Michael Bonin, Hjörvar Pétursson, Olaf Riess, David J. Burn, Steven Lubbe, J. Mark Cooper, Alisdair McNeill, Anthony Schapira, Codrin Lungu, Honglei Chen, Jing Dong, Patrick F. Chinnery, Gavin Hudson, Carl E. Clarke, Catriona Moorby, Carl Counsell, Philippe Damier, Jean François Dartigues, Panos Deloukas, Sarah Edkins, Sarah E. Hunt, Avazeh Tashakkori-Ghanbaria, Günther Deuschl, Delia Lorenz, David T. Dexter, Frank Durif, Jonathan R. Evans, Cordelia Langford, Thomas Foltynie, Alison Goate, Clare Harris, Jacobus J. van Hilten, Albert Hofman, Albert Hollenbeck, Janice Holton, Michele Hu, Xuemei Huang, Thomas Illig, Pálmi V. Jónsson, Jean Charles Lambert, Sean S. O'Sullivan, Tamas Revesz, Karen Shaw, Andrew Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Valentina Escott-Price, Justin Pearson, Nigel Williams, Ese Mudanohwo, Joel S. Perlmutter, Pierre Pollak, Fernando Rivadeneira, André G. Uitterlinden, Stephen Sawcer, Hans Scheffer, Ira Shoulson, Joshua Shulman, Colin Smith, Robert Walker, Chris C A Spencer, Amy Strange, Hreinn Stefánsson, Francesco Bettella, Kári Stefánsson, Joanna D. Stockton, Kevin Talbot, Carlie M. Tanner, François Tison, Sophie Winder-Rhodes, Kailash Bhatia

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

45 Citations (Scopus)
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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.

Original languageEnglish
Article number22
Number of pages26
JournalGenome Biology
Volume18
Issue number1
DOIs
Publication statusPublished - 30 Jan 2017

Keywords

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

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