@article{b0061a1f473d4f719335d69ef6bfc1f4,
title = "Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing",
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.",
keywords = "Animal model, Functional screening, Genomics, Loss-of-function, Mitochondria, Parkin, Parkinson's disease, Rare variants, Whole-exome sequencing, α-synuclein",
author = "{International Parkinson's Disease Genetics Consortium (IPGDC)} and Jansen, {Iris E.} and Hui Ye and Sasja Heetveld and Lechler, {Marie C.} and Helen Michels and Seinstra, {Ren{\'e}e I.} and Lubbe, {Steven J.} and Val{\'e}rie Drouet and Suzanne Lesage and Elisa Majounie and Gibbs, {J. Raphael} and Nalls, {Mike A.} and Mina Ryten and Botia, {Juan A.} and Jana Vandrovcova and Javier Simon-Sanchez and Melissa Castillo-Lizardo and Patrizia Rizzu and Cornelis Blauwendraat and Chouhan, {Amit K.} and Yarong Li and Puja Yogi and Najaf Amin and {van Duijn}, {Cornelia M.} and Morris, {Huw R.} and Alexis Brice and Singleton, {Andrew B.} and David, {Della C.} and Nollen, {Ellen A.} and Shushant Jain and Shulman, {Joshua M.} and Peter Heutink and Hernandez, {Dena G.} and Sampath Arepalli and Janet Brooks and Ryan Price and Aude Nicolas and Sean Chong and Cookson, {Mark R.} and Allissa Dillman and Matthew Moore and Traynor, {Bryan J.} and Singleton, {Andrew B.} and Vincent Plagnol and {Nicholas W Wood}, {W Wood} and Sheerin, {Una Marie} and {Jose M Bras}, {M Bras} and Gavin Charlesworth and Michelle Gardner and Perlmutter, {Joel S.}",
note = "Funding Information: 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{\textquoteright}s Disease Genetics Study (PDG), and the Drug Interaction with Genes in Parkinson{\textquoteright}s Disease (DIGPD) study. Data used in the preparation of this article were obtained from the Parkinson{\textquoteright}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 T{\"u}bingen 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 Sim{\'o}n-S{\'a}nchez (Genetics and Epigenetics of Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE)-T{\"u}bingen and Hertie Institute for Clinical Brain Research (HIH)), Claudia Schulte (Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research), Suzanne Lesage (Sorbonne Universit{\'e}, UPMC Univ Paris 06, UM 1127, ICM; Inserm, U 1127, ICM; Cnrs, UMR 7225, ICM; ICM, Paris), Sigurlaug Sveinbj{\"o}rnsd{\'o}ttir (Department of Neurology, Landsp{\'i}tali University Hospital, Reykjav{\'i}k, 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{\textquoteright}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 Funding Information: Funding for this study was provided by the Prinses Beatrix Spierfonds (IEJ, PH); the EU joint Program-Neurodegenerative Diseases (JPND): COURAGE-PD (PH, VD, SL, AB); the Federal Ministry of Education and Research Germany (BMBF): MitoPD (PH); NIH grants (K08AG034290, R21NS089854, R01AG033193, U01AG046161, C06RR029965, R01NS037167, R01CA141668, P50NS071674) (JMS, ABS); the Alzheimer{\textquoteright}s Association (JMS); the American Federation for Aging Research (JMS); Huffington Foundation (JMS); the Robert and Renee Belfer Family Foundation (JMS); the Jan and Dan Duncan Neurological Research Institute at Texas Children{\textquoteright}s Hospital (JMS); a Career Award for Medical Scientists from the Burroughs Wellcome Fund (JMS); the Wellcome Trust under awards 076113, 085475, and 090355 (SL, HM), Parkinson{\textquoteright}s UK (grants 8047, J-0804, F1002, and F-1201) (SL, HM); the Medical Research Council (G0700943 and G1100643) (SL, HM); the France-Parkinson Association (VD, SL, AB); the Roger de Spoelberch Foundation (R12123DD) (VD, SL, AB); the French Academy of Sciences (VD, SL, AB); the French program “Investissements d{\textquoteright}avenir” (ANR-10-IAIHU-06) (VD, SL, AB); the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services (ZO1 AG000957) (MN, JRG, ABS), the National Institute of Neurological Disorders and Stroke (NINDS) (Z01-AG000949-02), and the National Institute of Environmental Health Sciences (Z01-ES101986). Department of Defense (award W81XWH-09-2-0128); The Michael J Fox Foundation for Parkinson{\textquoteright}s Research; American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA; Hersenstichting Nederland; the German National Genome Network (NGFNplus number 01GS08134, German Ministry for Education and Research); the German Federal Ministry of Education and Research (NGFN 01GR0468, PopGen); 01EW0908 in the frame of ERA-NET NEURON and Helmholtz Alliance Mental Health in an Ageing Society (HA-215); European Community Framework Programme 7, People Programme; IAPP on novel genetic and phenotypic markers of Parkinson{\textquoteright}s disease, and Essential Tremor (MarkMD), contract number PIAP-GA-2008-230596 MarkMD. PPMI – a public–private partnership – is funded by the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research and funding partners, including Abbvie, Avid, Biogen, Bristol-Myers Squibb, Covance, GE Healthcare, Genentech, GlaxoSmithKline, Lilly, Lundbeek, Merck, Meso Scale Discovery, Pfizer, Piramal, Roche, Servier, Teva, UCB, and Golub Capital. The Pathology and Histology Core at Baylor College of Medicine is supported by NIH grant P30CA125123. The DIGPD cohort was sponsored by the Assistance Publique H{\^o}pitaux de Paris and founded by the French clinical research hospital program-PHRC (code AOR08010). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA (https://hpc.nih.gov/systems/) and DNA panels, samples, and clinical data from the National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository. The TRiP at Harvard Medical School, which provided fly stocks, is supported by R01GM084947. The relevant funding bodies (above) did not participate in the design of the study; collection, analysis, or interpretation of data; or in drafting the manuscript. Publisher Copyright: {\textcopyright} 2017 The Author(s).",
year = "2017",
month = jan,
day = "30",
doi = "10.1186/s13059-017-1147-9",
language = "English",
volume = "18",
journal = "Genome Biology",
issn = "1474-7596",
number = "1",
}