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

International Parkinson's Disease Genetics Consortium (IPGDC)

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

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 (US)
Article number22
JournalGenome biology
Volume18
Issue number1
DOIs
StatePublished - Jan 30 2017

Funding

We would like to thank all the participants who donated their time and biological samples to be a part of this study. This study was supported by the UK Brain Expression Consortium (UKBEC), the French Parkinson’s Disease Genetics Study (PDG), and the Drug Interaction with Genes in Parkinson’s Disease (DIGPD) study. Data used in the preparation of this article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org. We also thank the Bloomington Drosophila stock center, the Vienna Drosophila RNAi Center, and the TRiP at Harvard Medical School for providing fly strains. IPDGC consortium members and affiliations: Mike A Nalls (Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA), Vincent Plagnol (UCL Genetics Institute, London, UK), Dena G Hernandez (Laboratory of Neurogenetics, National Institute on Aging; and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK), Manu Sharma (Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry and Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen Germany), Una-Marie Sheerin (Department of Molecular Neuroscience, UCL Institute of Neurology), Mohamad Saad (INSERM U563, CPTP, Toulouse, France; and Paul Sabatier University, Toulouse, France), Javier Simón-Sánchez (Genetics and Epigenetics of Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE)-Tübingen and Hertie Institute for Clinical Brain Research (HIH)), Claudia Schulte (Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research), Suzanne Lesage (Sorbonne Université, UPMC Univ Paris 06, UM 1127, ICM; Inserm, U 1127, ICM; Cnrs, UMR 7225, ICM; ICM, Paris), Sigurlaug Sveinbjörnsdóttir (Department of Neurology, Landspítali University Hospital, Reykjavík, Iceland; Department of Neurology, MEHT Broomfield Hospital, Chelmsford, Essex, UK; and Queen Mary College, University of London, London, UK), Sampath Arepalli (Laboratory of Neurogenetics, National Institute on Aging), Roger Barker (Department of Neurology, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK), Yoav Ben-Shlomo (School of Social and Community Medicine, University of Bristol), Henk W Berendse (Department of Neurology and Alzheimer Center, VU University Medical Center), Daniela Berg (Department for Neurodegenerative

Keywords

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

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

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