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Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing
- Source :
- Genome Biology, 18:22, Genome Biology, 18, 1, pp. 22, Genome Biology, 18(22). BMC, 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, (IPGDC), I P D G C, Morris, H R, Brice, A, David, D C, Singleton, A B, Nollen, E A, Jain, S, Shulman, J M, Heutink, P, Burn, D J, Walker, R & Morrison, K 2017, ' Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing ', Genome biology, vol. 18, no. 22, pp. 1-26 . https://doi.org/10.1186/s13059-017-1147-9, Genome Biology, Jansen, I E, Ye, H, Heetveld, S, Lechler, M C, Michels, H, Seinstra, R I, Lubbe, S, 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 & International Parkinson's Disease Genetics Consortium (IPGDC) 2017, ' Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing ', Genome Biology, vol. 18, no. 1, 22 . https://doi.org/10.1186/s13059-017-1147-9, Genome Biology, 18, Genome biology 18(1), 22 (2017). doi:10.1186/s13059-017-1147-9, Genome Biology, 18, 22, Genome Biology, 18(1):22. BioMed Central Ltd., Genome biology, 18(1):22. BioMed Central, 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, Price, R, Nicolas, A, Chong, S, Cookson, M R, Dillman, A, Moore, M, Traynor, B J, Singleton, A B, Plagnol, V, Nicholas W Wood, W W, Sheerin, U M, Jose M Bras, M B, Charlesworth, G, Gardner, M, Guerreiro, R, Trabzuni, D, Hardy, J, Sharma, M, Saad, M, Javier Simón-Sánchez, S-S, Schulte, C, Corvol, J C, Dürr, A, Vidailhet, M, Sveinbjörnsdóttir, S, Barker, R, Caroline H Williams-Gray, H W-G, 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, Bloem, B, Post, B, Wickremaratchi, M, van de Warrenburg, B, Bochdanovits, Z, Bonin, M, Pétursson, H, Riess, O, Burn, D J, Lubbe, S, Cooper, J M, McNeill, A, Schapira, A, Lungu, C, Chen, H, Dong, J, Chinnery, P F, Hudson, G, Clarke, C E, Moorby, C, Counsell, C, Damier, P, Dartigues, J F, Deloukas, P, Edkins, S, Hunt, S E, Tashakkori-Ghanbaria, A, Deuschl, G, Lorenz, D, Dexter, D T, Durif, F, Evans, J R, Langford, C, Foltynie, T, Goate, A, Harris, C, van Hilten, J J, Hofman, A, Hollenbeck, A, Holton, J, Hu, M, Huang, X, Illig, T, Jónsson, P V, Lambert, J C, O'Sullivan, S S, Revesz, T, Shaw, K, Lees, A, Lichtner, P, Limousin, P, Lopez, G, Escott-Price, V, Pearson, J, Williams, N, Mudanohwo, E, Perlmutter, J S, Pollak, P, Rivadeneira, F, Uitterlinden, A G, Sawcer, S, Scheffer, H, Shoulson, I, Shulman, J, Smith, C, Walker, R, Spencer, C C A, Strange, A, Stefánsson, H, Bettella, F, Stefánsson, K, Stockton, J D, Talbot, K, Tanner, C M, Tison, F, Winder-Rhodes, S & Bhatia, K 2017, ' Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing ', Genome Biology, vol. 18, no. 1, 22 . https://doi.org/10.1186/s13059-017-1147-9
- Publication Year :
- 2017
-
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. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1147-9) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Candidate gene
G-PATCH
Parkinson's disease
methods [Sequence Analysis, DNA]
Compound heterozygosity
AXON GUIDANCE
Animals, Genetically Modified
DOMAIN-CONTAINING 2
genetics [Parkinson Disease]
Exome
Child
Cells, Cultured
Exome sequencing
Genetics
genetics [Drosophila melanogaster]
High-Throughput Nucleotide Sequencing
Parkinson Disease
Genomics
Middle Aged
Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3]
Mitochondria
ALZHEIMERS-DISEASE
Drosophila melanogaster
Whole-exome sequencing
genetics [alpha-Synuclein]
alpha-Synuclein
genetics [Caenorhabditis elegans]
RNA Interference
Adult
methods [High-Throughput Nucleotide Sequencing]
NETWORK ANALYSIS
Adolescent
Biology
Loss-of-function
Young Adult
03 medical and health sciences
α-synuclein
SDG 3 - Good Health and Well-being
ddc:570
Functional screening
Animals
Humans
Animal model
Genetic Predisposition to Disease
Allele
Caenorhabditis elegans
Parkin
RECEPTOR TYROSINE PHOSPHATASE
Research
RETROMER COMPLEX
Rare variants
Sequence Analysis, DNA
Human genetics
Retromer complex
DROSOPHILA MODEL
Disease Models, Animal
030104 developmental biology
Case-Control Studies
Parkinson’s disease
CAENORHABDITIS-ELEGANS
Subjects
Details
- ISSN :
- 1474760X, 14656906, and 14747596
- Database :
- OpenAIRE
- Journal :
- Genome Biology, 18:22, Genome Biology, 18, 1, pp. 22, Genome Biology, 18(22). BMC, 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, (IPGDC), I P D G C, Morris, H R, Brice, A, David, D C, Singleton, A B, Nollen, E A, Jain, S, Shulman, J M, Heutink, P, Burn, D J, Walker, R & Morrison, K 2017, ' Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing ', Genome biology, vol. 18, no. 22, pp. 1-26 . https://doi.org/10.1186/s13059-017-1147-9, Genome Biology, Jansen, I E, Ye, H, Heetveld, S, Lechler, M C, Michels, H, Seinstra, R I, Lubbe, S, 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 & International Parkinson's Disease Genetics Consortium (IPGDC) 2017, ' Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing ', Genome Biology, vol. 18, no. 1, 22 . https://doi.org/10.1186/s13059-017-1147-9, Genome Biology, 18, Genome biology 18(1), 22 (2017). doi:10.1186/s13059-017-1147-9, Genome Biology, 18, 22, Genome Biology, 18(1):22. BioMed Central Ltd., Genome biology, 18(1):22. BioMed Central, 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, Price, R, Nicolas, A, Chong, S, Cookson, M R, Dillman, A, Moore, M, Traynor, B J, Singleton, A B, Plagnol, V, Nicholas W Wood, W W, Sheerin, U M, Jose M Bras, M B, Charlesworth, G, Gardner, M, Guerreiro, R, Trabzuni, D, Hardy, J, Sharma, M, Saad, M, Javier Simón-Sánchez, S-S, Schulte, C, Corvol, J C, Dürr, A, Vidailhet, M, Sveinbjörnsdóttir, S, Barker, R, Caroline H Williams-Gray, H W-G, 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, Bloem, B, Post, B, Wickremaratchi, M, van de Warrenburg, B, Bochdanovits, Z, Bonin, M, Pétursson, H, Riess, O, Burn, D J, Lubbe, S, Cooper, J M, McNeill, A, Schapira, A, Lungu, C, Chen, H, Dong, J, Chinnery, P F, Hudson, G, Clarke, C E, Moorby, C, Counsell, C, Damier, P, Dartigues, J F, Deloukas, P, Edkins, S, Hunt, S E, Tashakkori-Ghanbaria, A, Deuschl, G, Lorenz, D, Dexter, D T, Durif, F, Evans, J R, Langford, C, Foltynie, T, Goate, A, Harris, C, van Hilten, J J, Hofman, A, Hollenbeck, A, Holton, J, Hu, M, Huang, X, Illig, T, Jónsson, P V, Lambert, J C, O'Sullivan, S S, Revesz, T, Shaw, K, Lees, A, Lichtner, P, Limousin, P, Lopez, G, Escott-Price, V, Pearson, J, Williams, N, Mudanohwo, E, Perlmutter, J S, Pollak, P, Rivadeneira, F, Uitterlinden, A G, Sawcer, S, Scheffer, H, Shoulson, I, Shulman, J, Smith, C, Walker, R, Spencer, C C A, Strange, A, Stefánsson, H, Bettella, F, Stefánsson, K, Stockton, J D, Talbot, K, Tanner, C M, Tison, F, Winder-Rhodes, S & Bhatia, K 2017, ' Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing ', Genome Biology, vol. 18, no. 1, 22 . https://doi.org/10.1186/s13059-017-1147-9
- Accession number :
- edsair.doi.dedup.....3c42a710738d9cbe1ee9c6b9ed4f6a6b