Journal
GENOME BIOLOGY
Volume 18, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13059-017-1147-9
Keywords
Parkinson's disease; Genomics; Whole-exome sequencing; Loss-of-function; Rare variants; Functional screening; Mitochondria; Parkin; alpha-synuclein; Animal model
Funding
- Prinses Beatrix Spierfonds
- EU joint Program-Neurodegenerative Diseases (JPND): COURAGE-PD
- Federal Ministry of Education and Research Germany (BMBF): MitoPD
- NIH [K08AG034290, R21NS089854, R01AG033193, U01AG046161, C06RR029965, R01NS037167, R01CA141668, P50NS071674, P30CA125123]
- Alzheimer's Association
- American Federation for Aging Research
- Huffington Foundation
- Robert and Renee Belfer Family Foundation
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital
- Burroughs Wellcome Fund
- Wellcome Trust [076113, 085475, 090355]
- Parkinson's UK [8047, J-0804, F1002, F-1201]
- Medical Research Council [G0700943, G1100643]
- France-Parkinson Association
- Roger de Spoelberch Foundation [R12123DD]
- French Academy of Sciences
- French program Investissements d'avenir [ANR-10-IAIHU-06]
- Intramural Research Program of the National Institute on Aging
- National Institutes of Health
- Department of Health and Human Services [ZO1 AG000957]
- National Institute of Neurological Disorders and Stroke (NINDS) [Z01-AG000949-02]
- National Institute of Environmental Health Sciences [Z01-ES101986]
- Department of Defense [W81XWH-09-2-0128]
- Michael J Fox Foundation for Parkinson's Research
- American Parkinson Disease Association (APDA)
- Bames Jewish Hospital Foundation
- Greater St Louis Chapter of the APDA
- Hersenstichting Nederland
- German National Genome Network (NGFNplus) [01GS08134]
- German Federal Ministry of Education and Research [NGFN 01GR0468]
- ERA-NET NEURON [01EW0908]
- Helmholtz Alliance Mental Health in an Ageing Society [HA-215]
- European Community Framework Programme 7
- People Programme
- IAPP on novel genetic and phenotypic markers of Parkinson's disease
- Essential Tremor [PIAP-GA-2008-230596]
- Michael J. Fox Foundation
- Abbvie
- Avid
- Biogen
- Bristol-Myers Squibb
- Covance
- GE Healthcare
- Genentech
- GlaxoSmithKline
- Lilly
- Lundbeek
- Merck
- Meso Scale Discovery
- Pfizer
- Piramal
- Roche
- Servier
- Teva
- UCB
- Golub Capital
- Assistance Publique Hopitaux de Paris
- TRiP at Harvard Medical School [R01GM084947]
- Medical Research Council [G0700943, G0802462, MR/K01417X/1, G1100643, MR/N008324/1] Funding Source: researchfish
- National Institute for Health Research [ACF-2012-17-017] Funding Source: researchfish
- Parkinson's UK [J-1403, K-1501, J-0901] Funding Source: researchfish
- MRC [MR/N008324/1, G1100643, MR/K01417X/1, G0802462, G0701075, G0700943] Funding Source: UKRI
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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 alpha-synucleininduced 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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