Faculty Collaboration Database

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing. Genome Biol 2017 Jan 30;18(1):22

Date

02/01/2017

Pubmed ID

28137300

Pubmed Central ID

PMC5282828

DOI

10.1186/s13059-017-1147-9

Scopus ID

2-s2.0-85011019247 (requires institutional sign-in at Scopus site)   87 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.

Author List

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, International Parkinson’s Disease Genetics Consortium (IPGDC), Morris HR, Brice A, Singleton AB, David DC, Nollen EA, Jain S, Shulman JM, Heutink P

Author

Jing Dong PhD Assistant Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Animals
Animals, Genetically Modified
Caenorhabditis elegans
Case-Control Studies
Cells, Cultured
Child
Disease Models, Animal
Drosophila melanogaster
Exome
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing
Humans
Middle Aged
Parkinson Disease
RNA Interference
Sequence Analysis, DNA
Young Adult
alpha-Synuclein