Leading science, pioneering therapies
CRM Publications

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

TitleDiscovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.
Publication TypeJournal Article
Year of Publication2017
AuthorsJansen IE, Ye H, Heetveld S, Lechler MC, Michels H, Seinstra RI, Lubbe SJ, Drouet V, Lesage S, Majounie E, J Gibbs R, 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
Corporate AuthorsInternational Parkinson’s Disease Genetics Consortium(IPGDC)
JournalGenome Biol
Volume18
Issue1
Pagination22
Date Published2017 Jan 30
ISSN1474-760X
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.

DOI10.1186/s13059-017-1147-9
Alternate JournalGenome Biol.
PubMed ID28137300
PubMed Central IDPMC5282828
Grant ListK08 AG034290 / AG / NIA NIH HHS / United States
Z01 AG000949 / AG / NIA NIH HHS / United States
R01 CA141668 / CA / NCI NIH HHS / United States
C06 RR029965 / RR / NCRR NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
R01 NS037167 / NS / NINDS NIH HHS / United States
R21 NS089854 / NS / NINDS NIH HHS / United States
U01 AG046161 / AG / NIA NIH HHS / United States
Z01 AG000957 / AG / NIA NIH HHS / United States
Z01 ES101986 / ES / NIEHS NIH HHS / United States
P50 NS071674 / NS / NINDS NIH HHS / United States
R01 GM084947 / GM / NIGMS NIH HHS / United States
Publication institute
Other