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; International Parkinson's Disease Genetics Consortium (IPGDC); Huw R. Morris; Alexis Brice; Andrew B. Singleton; Della C. David; Ellen A. Nollen; Shushant Jain; Joshua M. Shulman; Peter Heutink

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, International Parkinson's Disease Genetics Consortium (IPGDC), Huw R. Morris, Alexis Brice, Andrew B. Singleton, Della C. David, Ellen A. Nollen, Shushant Jain, Joshua M. Shulman^* (Corresponding Author), Peter Heutink^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

82 Citations (Scopus)

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
Journal	Genome Biology
Volume	18
Issue number	1
DOIs	https://doi.org/10.1186/s13059-017-1147-9
Publication status	Published - 30 Jan 2017
Externally published	Yes

Bibliographical note

Funding Information:
We would like to thank all the participants who donated their time and biological samples to be a part of this study. This study was supported by the UK Brain Expression Consortium (UKBEC), the French Parkinson’s Disease Genetics Study (PDG), and the Drug Interaction with Genes in Parkinson’s Disease (DIGPD) study. Data used in the preparation of this article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org. We also thank the Bloomington Drosophila stock center, the Vienna Drosophila RNAi Center, and the TRiP at Harvard Medical School for providing fly strains. IPDGC consortium members and affiliations: Mike A Nalls (Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA), Vincent Plagnol (UCL Genetics Institute, London, UK), Dena G Hernandez (Laboratory of Neurogenetics, National Institute on Aging; and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK), Manu Sharma (Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry and Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen Germany), Una-Marie Sheerin (Department of Molecular Neuroscience, UCL Institute of Neurology), Mohamad Saad (INSERM U563, CPTP, Toulouse, France; and Paul Sabatier University, Toulouse, France), Javier Simón-Sánchez (Genetics and Epigenetics of Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE)-Tübingen and Hertie Institute for Clinical Brain Research (HIH)), Claudia Schulte (Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research), Suzanne Lesage (Sorbonne Université, UPMC Univ Paris 06, UM 1127, ICM; Inserm, U 1127, ICM; Cnrs, UMR 7225, ICM; ICM, Paris), Sigurlaug Sveinbjörnsdóttir (Department of Neurology, Landspítali University Hospital, Reykjavík, Iceland; Department of Neurology, MEHT Broomfield Hospital, Chelmsford, Essex, UK; and Queen Mary College, University of London, London, UK), Sampath Arepalli (Laboratory of Neurogenetics, National Institute on Aging), Roger Barker (Department of Neurology, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK), Yoav Ben-Shlomo (School of Social and Community Medicine, University of Bristol), Henk W Berendse (Department of Neurology and Alzheimer Center, VU University Medical Center), Daniela Berg (Department for Neurodegenerative

Publisher Copyright:
© 2017 The Author(s).

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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10.1186/s13059-017-1147-9

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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., ... Heutink, P. (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

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 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

@article{2628246cc74d41aebdc33c7997da6699,

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 {International Parkinson's Disease Genetics Consortium (IPGDC)} 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 Carl Counsell",

note = "Funding Information: We would like to thank all the participants who donated their time and biological samples to be a part of this study. This study was supported by the UK Brain Expression Consortium (UKBEC), the French Parkinson{\textquoteright}s Disease Genetics Study (PDG), and the Drug Interaction with Genes in Parkinson{\textquoteright}s Disease (DIGPD) study. Data used in the preparation of this article were obtained from the Parkinson{\textquoteright}s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org. We also thank the Bloomington Drosophila stock center, the Vienna Drosophila RNAi Center, and the TRiP at Harvard Medical School for providing fly strains. IPDGC consortium members and affiliations: Mike A Nalls (Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA), Vincent Plagnol (UCL Genetics Institute, London, UK), Dena G Hernandez (Laboratory of Neurogenetics, National Institute on Aging; and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK), Manu Sharma (Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry and Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of T{\"u}bingen Germany), Una-Marie Sheerin (Department of Molecular Neuroscience, UCL Institute of Neurology), Mohamad Saad (INSERM U563, CPTP, Toulouse, France; and Paul Sabatier University, Toulouse, France), Javier Sim{\'o}n-S{\'a}nchez (Genetics and Epigenetics of Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE)-T{\"u}bingen and Hertie Institute for Clinical Brain Research (HIH)), Claudia Schulte (Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research), Suzanne Lesage (Sorbonne Universit{\'e}, UPMC Univ Paris 06, UM 1127, ICM; Inserm, U 1127, ICM; Cnrs, UMR 7225, ICM; ICM, Paris), Sigurlaug Sveinbj{\"o}rnsd{\'o}ttir (Department of Neurology, Landsp{\'i}tali University Hospital, Reykjav{\'i}k, Iceland; Department of Neurology, MEHT Broomfield Hospital, Chelmsford, Essex, UK; and Queen Mary College, University of London, London, UK), Sampath Arepalli (Laboratory of Neurogenetics, National Institute on Aging), Roger Barker (Department of Neurology, Addenbrooke{\textquoteright}s Hospital, University of Cambridge, Cambridge, UK), Yoav Ben-Shlomo (School of Social and Community Medicine, University of Bristol), Henk W Berendse (Department of Neurology and Alzheimer Center, VU University Medical Center), Daniela Berg (Department for Neurodegenerative Publisher Copyright: {\textcopyright} 2017 The Author(s).",

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",

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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 - International Parkinson's Disease Genetics Consortium (IPGDC)

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 - Counsell, Carl

N1 - Funding Information: We would like to thank all the participants who donated their time and biological samples to be a part of this study. This study was supported by the UK Brain Expression Consortium (UKBEC), the French Parkinson’s Disease Genetics Study (PDG), and the Drug Interaction with Genes in Parkinson’s Disease (DIGPD) study. Data used in the preparation of this article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org. We also thank the Bloomington Drosophila stock center, the Vienna Drosophila RNAi Center, and the TRiP at Harvard Medical School for providing fly strains. IPDGC consortium members and affiliations: Mike A Nalls (Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA), Vincent Plagnol (UCL Genetics Institute, London, UK), Dena G Hernandez (Laboratory of Neurogenetics, National Institute on Aging; and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK), Manu Sharma (Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry and Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen Germany), Una-Marie Sheerin (Department of Molecular Neuroscience, UCL Institute of Neurology), Mohamad Saad (INSERM U563, CPTP, Toulouse, France; and Paul Sabatier University, Toulouse, France), Javier Simón-Sánchez (Genetics and Epigenetics of Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE)-Tübingen and Hertie Institute for Clinical Brain Research (HIH)), Claudia Schulte (Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research), Suzanne Lesage (Sorbonne Université, UPMC Univ Paris 06, UM 1127, ICM; Inserm, U 1127, ICM; Cnrs, UMR 7225, ICM; ICM, Paris), Sigurlaug Sveinbjörnsdóttir (Department of Neurology, Landspítali University Hospital, Reykjavík, Iceland; Department of Neurology, MEHT Broomfield Hospital, Chelmsford, Essex, UK; and Queen Mary College, University of London, London, UK), Sampath Arepalli (Laboratory of Neurogenetics, National Institute on Aging), Roger Barker (Department of Neurology, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK), Yoav Ben-Shlomo (School of Social and Community Medicine, University of Bristol), Henk W Berendse (Department of Neurology and Alzheimer Center, VU University Medical Center), Daniela Berg (Department for Neurodegenerative Publisher Copyright: © 2017 The Author(s).

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

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DO - 10.1186/s13059-017-1147-9

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AN - SCOPUS:85011019247

SN - 1474-7596

VL - 18

JO - Genome Biology

JF - Genome Biology

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M1 - 22

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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