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

Abstract

BackgroundWhole-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.ResultsAssuming 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.ConclusionsBy 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1147-9) contains supplementary material, which is available to authorized users.

Yeast and other lower eukaryotic organisms for studies of Vps13 proteins in health and disease

“…The hVps13C protein is enriched in the outer membrane of mitochondria, lipid droplets and, based on cell fractionation studies, in early endosomes . The hVps13C protein may also be involved in maintenance of mitochondrial morphology and vulnerability to stress . Furthermore, hVps13C participates in adipogenesis by binding galectin‐12, a protein required for adipogenic signaling and adipocyte differentiation in vitro .…”

Understanding the role of genetic variability in LRRK2 in Indian population

“…For individual QC in both the WES and the NeuroX data sets, samples were removed when showing sex ambiguity, dubious heterozygosity/genotype calls, evidence of relatedness, or being a population outlier. Further details of the cohort were described elsewhere . For COURAGE‐PD data, we leveraged the results from targeted resequencing of European (800 PD cases and 800 controls) and Korean (690 PD patients and 690 controls) cohorts .…”

Progress toward an integrated understanding of Parkinson’s disease

“…Medium- to high-throughput screening assays in cellular or animal models can connect promising candidate genes to PD-relevant biologic mechanisms, prioritizing a subset for further study. For example, Jansen et al 9 evaluated 27 promising candidate genes with homozygous or compound heterozygous loss-of-function alleles based on WES in 1,148 unrelated young-onset PD cases. Since nearly all of the gene candidates were observed only once in the cohort, the investigators probed each gene for roles in mitochondrial dynamics or α-Syn-mediated toxicity using cellular and fruit fly experimental models.…”