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Jansen, I.E.* ; Ye, H.* ; Heetveld, S.* ; Lechler, M.C.* ; Michels, H.* ; Seinstra, R.I.* ; Lubbe, S.J.* ; Drouet, V.* ; Lesage, S.* ; Majounie, E.* ; Gibbs, J.R.* ; Nalls, M.A.* ; Ryten, M.* ; Botia, J.A.* ; Vandrovcova, J.* ; Simon-Sanchez, J.* ; Castillo-Lizardo, M.* ; Rizzu, P.* ; Blauwendraat, C.* ; Chouhan, A.K.* ; Li, Y.* ; Yogi, P.* ; Amin, N.* ; van Duijn, C.M.* ; Morris, H.R.* ; Brice, A.* ; Singleton, A.B.* ; David, D.C.* ; Nollen, E.A.* ; Jain, S.* ; Shulman, J.M.* ; Heutink, P.* ; Hernandez, D.G.* ; Arepalli, S.* ; Brooks, J.M.* ; Price, R.* ; Nicolas, A.* ; Chong, S.* ; Cookson, M.R.* ; Dillman, A.* ; Moore, M.* ; Traynor, B.J.* ; Plagnol, V.* ; Nicholas W Wood,* ; Sheerin, U.M.* ; Jose M Bras,* ; Charlesworth, G.* ; Gardner, M.* ; Guerreiro, R.* ; Trabzuni, D.* ; Hardy, J.* ; International Parkinson's Disease Genomics Consortium (IPDGC) (Illig, T. ; Lichtner, P.) ; Schulte, C.* ; Corvol, J.C.* ; Dürr, A.* ; Vidailhet, M.* ; Sveinbjörnsdóttir, S.* ; Barker, R.A.* ; Williams-Gray, C.H.* ; Ben-Shlomo, Y.* ; Berendse, H.W.* ; van Dijk, K.D.* ; Berg, D.* ; Brockmann, K.* ; Wurster, I.* ; Mätzler, W.* ; Gasser, T.* ; Martinez, M.* ; de Bie, R.M.A.* ; Biffi, A.* ; Velseboer, D.*

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

Genome Biol. 18:22 (2017)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Animal Model ; Functional Screening ; Genomics ; Loss-of-function ; Mitochondria ; Parkin ; Parkinson's Disease ; Rare Variants ; Whole-exome Sequencing ; α-synuclein
Sprache
Veröffentlichungsjahr 2017
HGF-Berichtsjahr 2017
ISSN (print) / ISBN 1474-760X
e-ISSN 1465-6906
Zeitschrift Genome Biology
Quellenangaben Band: 18, Heft: 1, Seiten: , Artikelnummer: 22 Supplement: ,
Verlag BioMed Central
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology (EPI)
Institute of Human Genetics (IHG)
POF Topic(s) 30202 - Environmental Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-504091-001
G-500700-001
PubMed ID 28137300
DOI 10.1186/s13059-017-1147-9
Scopus ID 85011019247
Erfassungsdatum 2017-03-07
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