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Lookup NU author(s): Professor David Burn, Professor Patrick Chinnery, Professor Gavin Hudson
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2017 The Author(s). 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.
Author(s): Jansen IE, Ye H, Heetveld S, Lechler MC, Michels H, Seinstra RI, Lubbe SJ, Drouet V, Lesage S, Majounie E, Gibbs JR, Nalls MA, Ryten M, Botia JA, Vandrovcova J, Simon-Sanchez J, Castillo-Lizardo M, Rizzu P, Blauwendraat C, Chouhan AK, Li Y, Yogi P, Amin N, van Duijn CM, Morris HR, Brice A, Singleton AB, David DC, Nollen EA, Jain S, Shulman JM, Heutink P, Hernandez DG, Arepalli S, Brooks J, Price R, Nicolas A, Chong S, Cookson MR, Dillman A, Moore M, Traynor BJ, Singleton, Plagnol V, Wood NW, Sheerin U-M, Bras JM, Charlesworth G, Gardner M, Guerreiro R, Trabzuni D, Hardy J, Sharma M, Saad M, Simon-Sanchez J, Schulte C, Corvol JC, Durr A, Vidailhet M, Sveinbjornsdottir S, Barker R, Williams-Gray CH, Ben-Shlomo Y, Berendse HW, van Dijk KD, Berg D, Brockmann K, Wurster I, Matzler W, Gasser T, Martinez M, de Bie RMA, Biffi A, Velseboer D, Bloem B, Post B, Wickremaratchi M, van de Warrenburg B, Bochdanovits Z, Bonin M, Petursson H, Riess O, Burn DJ, Lubbe S, Cooper JM, McNeill A, Schapira A, Lungu C, Chen H, Dong J, Chinnery PF, Hudson G, Clarke CE, Moorby C, Counsell C, Damier P, Dartigues J-F, Deloukas P, Gray E, Edkins S, Hunt SE, Potter S, Tashakkori-Ghanbaria A, Deuschl G, Lorenz D, Dexter DT, Durif F, Evans JR, Langford C, Foltynie T, Goate A, Harris C, van Hilten JJ, Hofman A, Hollenbeck A, Holton J, Hu M, Huang X, Illig T, Jonsson PV, Lambert J-C, O'Sullivan SS, Revesz T, Shaw K, Lees A, Lichtner P, Limousin P, Lopez G, Escott-Price V, Pearson J, Williams N, Mudanohwo E, Perlmutter JS, Pollak P, Rivadeneira F, Uitterlinden AG, Sawcer S, Scheffer H, Shoulson I, Shulman J, Smith C, Walker R, Spencer CCA, Strange A, Stefansson H, Bettella F, Stefansson K, Stockton JD, Talbot K, Tanner CM, Tison F, Winder-Rhodes S, Bhatia K
Publication type: Article
Publication status: Published
Journal: Genome Biology
Year: 2017
Volume: 18
Online publication date: 30/01/2017
Acceptance date: 03/01/2017
Date deposited: 07/12/2017
ISSN (print): 1474-7596
ISSN (electronic): 1474-760X
Publisher: BioMed Central Ltd
URL: https://doi.org/10.1186/s13059-017-1147-9
DOI: 10.1186/s13059-017-1147-9
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