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

Iris E. Jansen; Hui Ye; Sasja Heetveld; Marie C. Lechler; Helen Michels; Renée I. Seinstra; Steven J. Lubbe; Valérie Drouet; Suzanne Lesage; Elisa Majounie; J. Raphael Gibbs; Mike A. Nalls; Mina Ryten; Juan A. Botia; Jana Vandrovcova; Javier Simon-Sanchez; Melissa Castillo-Lizardo; Patrizia Rizzu; Cornelis Blauwendraat; Amit K. Chouhan; Yarong Li; Puja Yogi; Najaf Amin; Cornelia M. van Duijn; Huw R. Morris; Alexis Brice; Andrew B. Singleton; Della C. David; Ellen A. Nollen; Shushant Jain; Joshua M. Shulman; Peter Heutink; Dena G. Hernandez; Sampath Arepalli; Janet Brooks; Ryan Price; Aude Nicolas; Sean Chong; Mark R. Cookson; Allissa Dillman; Matthew Moore; Bryan J. Traynor; Andrew B. Singleton; Vincent Plagnol; W Wood Nicholas W Wood; Una Marie Sheerin; M Bras Jose M Bras; Gavin Charlesworth; Michelle Gardner; Rita Guerreiro; Daniah Trabzuni; John Hardy; Manu Sharma; Mohamad Saad; Simón-Sánchez Javier Simón-Sánchez; Claudia Schulte; Jean Christophe Corvol; Alexandra Dürr; Marie Vidailhet; Sigurlaug Sveinbjörnsdóttir; Roger Barker; H Williams-Gray Caroline H Williams-Gray; Yoav Ben-Shlomo; Henk W. Berendse; Karin D. van Dijk; Daniela Berg; Kathrin Brockmann; Isabel Wurster; Walter Mätzler; Thomas Gasser; Maria Martinez; Rob M A de Bie; Alessandro Biffi; Daan Velseboer; Bas Bloem; Bart Post; Mirdhu Wickremaratchi; Bart van de Warrenburg; Zoltan Bochdanovits; Michael Bonin; Hjörvar Pétursson; Olaf Riess; David J. Burn; Steven Lubbe; J. Mark Cooper; Alisdair McNeill; Anthony Schapira; Codrin Lungu; Honglei Chen; Jing Dong; Patrick F. Chinnery; Gavin Hudson; Carl E. Clarke; Catriona Moorby; Carl Counsell; Philippe Damier; Jean François Dartigues; Panos Deloukas; Sarah Edkins; Sarah E. Hunt; Avazeh Tashakkori-Ghanbaria; Günther Deuschl; Delia Lorenz; David T. Dexter; Frank Durif; Jonathan R. Evans; Cordelia Langford; Thomas Foltynie; Alison Goate; Clare Harris; Jacobus J. van Hilten; Albert Hofman; Albert Hollenbeck; Janice Holton; Michele Hu; Xuemei Huang; Thomas Illig; Pálmi V. Jónsson; Jean Charles Lambert; Sean S. O'Sullivan; Tamas Revesz; Karen Shaw; Andrew Lees; Peter Lichtner; Patricia Limousin; Grisel Lopez; Valentina Escott-Price; Justin Pearson; Nigel Williams; Ese Mudanohwo; Joel S. Perlmutter; Pierre Pollak; Fernando Rivadeneira; André G. Uitterlinden; Stephen Sawcer; Hans Scheffer; Ira Shoulson; Joshua Shulman; Colin Smith; Robert Walker; Chris C A Spencer; Amy Strange; Hreinn Stefánsson; Francesco Bettella; Kári Stefánsson; Joanna D. Stockton; Kevin Talbot; Carlie M. Tanner; François Tison; Sophie Winder-Rhodes; Kailash Bhatia

doi:10.1186/s13059-017-1147-9

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

Iris E. Jansen, Hui Ye, Sasja Heetveld, Marie C. Lechler, Helen Michels, Renée I. Seinstra, Steven J. Lubbe, Valérie Drouet, Suzanne Lesage, Elisa Majounie, J. Raphael Gibbs, Mike A. Nalls, Mina Ryten, Juan A. Botia, Jana Vandrovcova, Javier Simon-Sanchez, Melissa Castillo-Lizardo, Patrizia Rizzu, Cornelis Blauwendraat, Amit K. ChouhanYarong Li, Puja Yogi, Najaf Amin, Cornelia M. van Duijn, Huw R. Morris, Alexis Brice, Andrew B. Singleton, Della C. David, Ellen A. Nollen, Shushant Jain, Joshua M. Shulman^*, Peter Heutink, Dena G. Hernandez, Sampath Arepalli, Janet Brooks, Ryan Price, Aude Nicolas, Sean Chong, Mark R. Cookson, Allissa Dillman, Matthew Moore, Bryan J. Traynor, Andrew B. Singleton, Vincent Plagnol, W Wood Nicholas W Wood, Una Marie Sheerin, M Bras Jose M Bras, Gavin Charlesworth, Michelle Gardner, Rita Guerreiro, Daniah Trabzuni, John Hardy, Manu Sharma, Mohamad Saad, Simón-Sánchez Javier Simón-Sánchez, Claudia Schulte, Jean Christophe Corvol, Alexandra Dürr, Marie Vidailhet, Sigurlaug Sveinbjörnsdóttir, Roger Barker, H Williams-Gray Caroline H Williams-Gray, Yoav Ben-Shlomo, Henk W. Berendse, Karin D. van Dijk, Daniela Berg, Kathrin Brockmann, Isabel Wurster, Walter Mätzler, Thomas Gasser, Maria Martinez, Rob M A de Bie, Alessandro Biffi, Daan Velseboer, Bas Bloem, Bart Post, Mirdhu Wickremaratchi, Bart van de Warrenburg, Zoltan Bochdanovits, Michael Bonin, Hjörvar Pétursson, Olaf Riess, David J. Burn, Steven Lubbe, J. Mark Cooper, Alisdair McNeill, Anthony Schapira, Codrin Lungu, Honglei Chen, Jing Dong, Patrick F. Chinnery, Gavin Hudson, Carl E. Clarke, Catriona Moorby, Carl Counsell, Philippe Damier, Jean François Dartigues, Panos Deloukas, Sarah Edkins, Sarah E. Hunt, Avazeh Tashakkori-Ghanbaria, Günther Deuschl, Delia Lorenz, David T. Dexter, Frank Durif, Jonathan R. Evans, Cordelia Langford, Thomas Foltynie, Alison Goate, Clare Harris, Jacobus J. van Hilten, Albert Hofman, Albert Hollenbeck, Janice Holton, Michele Hu, Xuemei Huang, Thomas Illig, Pálmi V. Jónsson, Jean Charles Lambert, Sean S. O'Sullivan, Tamas Revesz, Karen Shaw, Andrew Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Valentina Escott-Price, Justin Pearson, Nigel Williams, Ese Mudanohwo, Joel S. Perlmutter, Pierre Pollak, Fernando Rivadeneira, André G. Uitterlinden, Stephen Sawcer, Hans Scheffer, Ira Shoulson, Joshua Shulman, Colin Smith, Robert Walker, Chris C A Spencer, Amy Strange, Hreinn Stefánsson, Francesco Bettella, Kári Stefánsson, Joanna D. Stockton, Kevin Talbot, Carlie M. Tanner, François Tison, Sophie Winder-Rhodes, Kailash Bhatia

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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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.

Original language	English
Article number	22
Number of pages	26
Journal	Genome Biology
Volume	18
Issue number	1
DOIs	https://doi.org/10.1186/s13059-017-1147-9
Publication status	Published - 30 Jan 2017

Keywords

Animal model
Functional screening
Genomics
Loss-of-function
Mitochondria
Parkin
Parkinson's disease
Rare variants
Whole-exome sequencing
α-synuclein

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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., ... Bhatia, K. (2017). Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing. Genome Biology, 18(1), Article 22. https://doi.org/10.1186/s13059-017-1147-9

@article{79108d1e1e5e4dee8591ba8caf5ddfc7,

title = "Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing",

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.",

keywords = "Animal model, Functional screening, Genomics, Loss-of-function, Mitochondria, Parkin, Parkinson's disease, Rare variants, Whole-exome sequencing, α-synuclein",

author = "Jansen, {Iris E.} and Hui Ye and Sasja Heetveld and Lechler, {Marie C.} and Helen Michels and Seinstra, {Ren{\'e}e I.} and Lubbe, {Steven J.} and Val{\'e}rie Drouet and Suzanne Lesage and Elisa Majounie and Gibbs, {J. Raphael} and Nalls, {Mike A.} and Mina Ryten and Botia, {Juan A.} and Jana Vandrovcova and Javier Simon-Sanchez and Melissa Castillo-Lizardo and Patrizia Rizzu and Cornelis Blauwendraat and Chouhan, {Amit K.} and Yarong Li and Puja Yogi and Najaf Amin and {van Duijn}, {Cornelia M.} and Morris, {Huw R.} and Alexis Brice and Singleton, {Andrew B.} and David, {Della C.} and Nollen, {Ellen A.} and Shushant Jain and Shulman, {Joshua M.} and Peter Heutink and Hernandez, {Dena G.} and Sampath Arepalli and Janet Brooks and Ryan Price and Aude Nicolas and Sean Chong and Cookson, {Mark R.} and Allissa Dillman and Matthew Moore and Traynor, {Bryan J.} and Singleton, {Andrew B.} and Vincent Plagnol and {Nicholas W Wood}, {W Wood} and Sheerin, {Una Marie} and {Jose M Bras}, {M Bras} and Gavin Charlesworth and Michelle Gardner and Rita Guerreiro and Daniah Trabzuni and John Hardy and Manu Sharma and Mohamad Saad and {Javier Sim{\'o}n-S{\'a}nchez}, Sim{\'o}n-S{\'a}nchez and Claudia Schulte and Corvol, {Jean Christophe} and Alexandra D{\"u}rr and Marie Vidailhet and Sigurlaug Sveinbj{\"o}rnsd{\'o}ttir and Roger Barker and {Caroline H Williams-Gray}, {H Williams-Gray} and Yoav Ben-Shlomo and Berendse, {Henk W.} and {van Dijk}, {Karin D.} and Daniela Berg and Kathrin Brockmann and Isabel Wurster and Walter M{\"a}tzler and Thomas Gasser and Maria Martinez and {de Bie}, {Rob M A} and Alessandro Biffi and Daan Velseboer and Bas Bloem and Bart Post and Mirdhu Wickremaratchi and {van de Warrenburg}, Bart and Zoltan Bochdanovits and Michael Bonin and Hj{\"o}rvar P{\'e}tursson and Olaf Riess and Burn, {David J.} and Steven Lubbe and Cooper, {J. Mark} and Alisdair McNeill and Anthony Schapira and Codrin Lungu and Honglei Chen and Jing Dong and Chinnery, {Patrick F.} and Gavin Hudson and Clarke, {Carl E.} and Catriona Moorby and Carl Counsell and Philippe Damier and Dartigues, {Jean Fran{\c c}ois} and Panos Deloukas and Sarah Edkins and Hunt, {Sarah E.} and Avazeh Tashakkori-Ghanbaria and G{\"u}nther Deuschl and Delia Lorenz and Dexter, {David T.} and Frank Durif and Evans, {Jonathan R.} and Cordelia Langford and Thomas Foltynie and Alison Goate and Clare Harris and {van Hilten}, {Jacobus J.} and Albert Hofman and Albert Hollenbeck and Janice Holton and Michele Hu and Xuemei Huang and Thomas Illig and J{\'o}nsson, {P{\'a}lmi V.} and Lambert, {Jean Charles} and O'Sullivan, {Sean S.} and Tamas Revesz and Karen Shaw and Andrew Lees and Peter Lichtner and Patricia Limousin and Grisel Lopez and Valentina Escott-Price and Justin Pearson and Nigel Williams and Ese Mudanohwo and Perlmutter, {Joel S.} and Pierre Pollak and Fernando Rivadeneira and Uitterlinden, {Andr{\'e} G.} and Stephen Sawcer and Hans Scheffer and Ira Shoulson and Joshua Shulman and Colin Smith and Robert Walker and Spencer, {Chris C A} and Amy Strange and Hreinn Stef{\'a}nsson and Francesco Bettella and K{\'a}ri Stef{\'a}nsson and Stockton, {Joanna D.} and Kevin Talbot and Tanner, {Carlie M.} and Fran{\c c}ois Tison and Sophie Winder-Rhodes and Kailash Bhatia",

year = "2017",

month = jan,

day = "30",

doi = "10.1186/s13059-017-1147-9",

language = "English",

volume = "18",

journal = "Genome Biology",

issn = "1474-7596",

publisher = "BioMed Central",

number = "1",

}

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, Morris, HR, Brice, A, Singleton, AB, David, DC, Nollen, EA, Jain, S, Shulman, JM, Heutink, P, Hernandez, DG, Arepalli, S, Brooks, J, Price, R, Nicolas, A, Chong, S, Cookson, MR, Dillman, A, Moore, M, Traynor, BJ, Singleton, AB, Plagnol, V, Nicholas W Wood, WW, Sheerin, UM, Jose M Bras, MB, Charlesworth, G, Gardner, M, Guerreiro, R, Trabzuni, D, Hardy, J, Sharma, M, Saad, M, Javier Simón-Sánchez, S-S, Schulte, C, Corvol, JC, Dürr, A, Vidailhet, M, Sveinbjörnsdóttir, S, Barker, R, Caroline H Williams-Gray, HW-G, Ben-Shlomo, Y, Berendse, HW, van Dijk, KD, Berg, D, Brockmann, K, Wurster, I, Mätzler, W, Gasser, T, Martinez, M, de Bie, RMA, Biffi, A, Velseboer, D, Bloem, B, Post, B, Wickremaratchi, M, van de Warrenburg, B, Bochdanovits, Z, Bonin, M, Pétursson, H, Riess, O, Burn, DJ, Lubbe, S, Cooper, JM, McNeill, A, Schapira, A, Lungu, C, Chen, H, Dong, J, Chinnery, PF, Hudson, G, Clarke, CE, Moorby, C, Counsell, C, Damier, P, Dartigues, JF, Deloukas, P, Edkins, S, Hunt, SE, Tashakkori-Ghanbaria, A, Deuschl, G, Lorenz, D, Dexter, DT, Durif, F, Evans, JR, Langford, C, Foltynie, T, Goate, A, Harris, C, van Hilten, JJ, Hofman, A, Hollenbeck, A, Holton, J, Hu, M, Huang, X, Illig, T, Jónsson, PV, Lambert, JC, O'Sullivan, SS, Revesz, T, Shaw, K, Lees, A, Lichtner, P, Limousin, P, Lopez, G, Escott-Price, V, Pearson, J, Williams, N, Mudanohwo, E, Perlmutter, JS, Pollak, P, Rivadeneira, F, Uitterlinden, AG, Sawcer, S, Scheffer, H, Shoulson, I, Shulman, J, Smith, C, Walker, R, Spencer, CCA, Strange, A, Stefánsson, H, Bettella, F, Stefánsson, K, Stockton, JD, Talbot, K, Tanner, CM, 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

TY - JOUR

T1 - Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing

AU - Jansen, Iris E.

AU - Ye, Hui

AU - Heetveld, Sasja

AU - Lechler, Marie C.

AU - Michels, Helen

AU - Seinstra, Renée I.

AU - Lubbe, Steven J.

AU - Drouet, Valérie

AU - Lesage, Suzanne

AU - Majounie, Elisa

AU - Gibbs, J. Raphael

AU - Nalls, Mike A.

AU - Ryten, Mina

AU - Botia, Juan A.

AU - Vandrovcova, Jana

AU - Simon-Sanchez, Javier

AU - Castillo-Lizardo, Melissa

AU - Rizzu, Patrizia

AU - Blauwendraat, Cornelis

AU - Chouhan, Amit K.

AU - Li, Yarong

AU - Yogi, Puja

AU - Amin, Najaf

AU - van Duijn, Cornelia M.

AU - Morris, Huw R.

AU - Brice, Alexis

AU - Singleton, Andrew B.

AU - David, Della C.

AU - Nollen, Ellen A.

AU - Jain, Shushant

AU - Shulman, Joshua M.

AU - Heutink, Peter

AU - Hernandez, Dena G.

AU - Arepalli, Sampath

AU - Brooks, Janet

AU - Price, Ryan

AU - Nicolas, Aude

AU - Chong, Sean

AU - Cookson, Mark R.

AU - Dillman, Allissa

AU - Moore, Matthew

AU - Traynor, Bryan J.

AU - Singleton, Andrew B.

AU - Plagnol, Vincent

AU - Nicholas W Wood, W Wood

AU - Sheerin, Una Marie

AU - Jose M Bras, M Bras

AU - Charlesworth, Gavin

AU - Gardner, Michelle

AU - Guerreiro, Rita

AU - Trabzuni, Daniah

AU - Hardy, John

AU - Sharma, Manu

AU - Saad, Mohamad

AU - Javier Simón-Sánchez, Simón-Sánchez

AU - Schulte, Claudia

AU - Corvol, Jean Christophe

AU - Dürr, Alexandra

AU - Vidailhet, Marie

AU - Sveinbjörnsdóttir, Sigurlaug

AU - Barker, Roger

AU - Caroline H Williams-Gray, H Williams-Gray

AU - Ben-Shlomo, Yoav

AU - Berendse, Henk W.

AU - van Dijk, Karin D.

AU - Berg, Daniela

AU - Brockmann, Kathrin

AU - Wurster, Isabel

AU - Mätzler, Walter

AU - Gasser, Thomas

AU - Martinez, Maria

AU - de Bie, Rob M A

AU - Biffi, Alessandro

AU - Velseboer, Daan

AU - Bloem, Bas

AU - Post, Bart

AU - Wickremaratchi, Mirdhu

AU - van de Warrenburg, Bart

AU - Bochdanovits, Zoltan

AU - Bonin, Michael

AU - Pétursson, Hjörvar

AU - Riess, Olaf

AU - Burn, David J.

AU - Lubbe, Steven

AU - Cooper, J. Mark

AU - McNeill, Alisdair

AU - Schapira, Anthony

AU - Lungu, Codrin

AU - Chen, Honglei

AU - Dong, Jing

AU - Chinnery, Patrick F.

AU - Hudson, Gavin

AU - Clarke, Carl E.

AU - Moorby, Catriona

AU - Counsell, Carl

AU - Damier, Philippe

AU - Dartigues, Jean François

AU - Deloukas, Panos

AU - Edkins, Sarah

AU - Hunt, Sarah E.

AU - Tashakkori-Ghanbaria, Avazeh

AU - Deuschl, Günther

AU - Lorenz, Delia

AU - Dexter, David T.

AU - Durif, Frank

AU - Evans, Jonathan R.

AU - Langford, Cordelia

AU - Foltynie, Thomas

AU - Goate, Alison

AU - Harris, Clare

AU - van Hilten, Jacobus J.

AU - Hofman, Albert

AU - Hollenbeck, Albert

AU - Holton, Janice

AU - Hu, Michele

AU - Huang, Xuemei

AU - Illig, Thomas

AU - Jónsson, Pálmi V.

AU - Lambert, Jean Charles

AU - O'Sullivan, Sean S.

AU - Revesz, Tamas

AU - Shaw, Karen

AU - Lees, Andrew

AU - Lichtner, Peter

AU - Limousin, Patricia

AU - Lopez, Grisel

AU - Escott-Price, Valentina

AU - Pearson, Justin

AU - Williams, Nigel

AU - Mudanohwo, Ese

AU - Perlmutter, Joel S.

AU - Pollak, Pierre

AU - Rivadeneira, Fernando

AU - Uitterlinden, André G.

AU - Sawcer, Stephen

AU - Scheffer, Hans

AU - Shoulson, Ira

AU - Shulman, Joshua

AU - Smith, Colin

AU - Walker, Robert

AU - Spencer, Chris C A

AU - Strange, Amy

AU - Stefánsson, Hreinn

AU - Bettella, Francesco

AU - Stefánsson, Kári

AU - Stockton, Joanna D.

AU - Talbot, Kevin

AU - Tanner, Carlie M.

AU - Tison, François

AU - Winder-Rhodes, Sophie

AU - Bhatia, Kailash

PY - 2017/1/30

Y1 - 2017/1/30

N2 - 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.

AB - 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.

KW - Animal model

KW - Functional screening

KW - Genomics

KW - Loss-of-function

KW - Mitochondria

KW - Parkin

KW - Parkinson's disease

KW - Rare variants

KW - Whole-exome sequencing

KW - α-synuclein

U2 - 10.1186/s13059-017-1147-9

DO - 10.1186/s13059-017-1147-9

M3 - Article (Academic Journal)

C2 - 28137300

AN - SCOPUS:85011019247

SN - 1474-7596

VL - 18

JO - Genome Biology

JF - Genome Biology

IS - 1

M1 - 22

ER -

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

Abstract

Keywords

UN SDGs

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