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 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 & 13 others 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, International Parkinson's Disease Genetics Consortium (IPGDC)

Research output: Contribution to journalArticleAcademicpeer-review

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 languageEnglish
Article number22
JournalGenome Biology
Volume18
Issue number1
DOIs
Publication statusPublished - 30 Jan 2017

Cite this

Jansen, I. E., Ye, H., Heetveld, S., Lechler, M. C., Michels, H., Seinstra, R. I., ... 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, 18(1), [22]. https://doi.org/10.1186/s13059-017-1147-9
Jansen, Iris E. ; Ye, Hui ; Heetveld, Sasja ; Lechler, Marie C. ; Michels, Helen ; Seinstra, Renée I. ; Lubbe, Steven ; Drouet, Valérie ; Lesage, Suzanne ; Majounie, Elisa ; Gibbs, J. Raphael ; Nalls, Mike A. ; Ryten, Mina ; Botia, Juan A. ; Vandrovcova, Jana ; Simon-Sanchez, Javier ; Castillo-Lizardo, Melissa ; Rizzu, Patrizia ; Blauwendraat, Cornelis ; Chouhan, Amit K. ; Li, Yarong ; Yogi, Puja ; Amin, Najaf ; van Duijn, Cornelia M. ; Morris, Huw R. ; Brice, Alexis ; Singleton, Andrew B. ; David, Della C. ; Nollen, Ellen A. ; Jain, Shushant ; Shulman, Joshua M. ; Heutink, Peter ; International Parkinson's Disease Genetics Consortium (IPGDC). / Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing. In: Genome Biology. 2017 ; Vol. 18, No. 1.
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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 Steven Lubbe 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 Berendse, {Henk W.} and {van Dijk}, {Karin D.} and Zoltan Bochdanovits and {International Parkinson's Disease Genetics Consortium (IPGDC)}",
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Jansen, IE, Ye, H, Heetveld, S, Lechler, MC, Michels, H, Seinstra, RI, Lubbe, S, 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 & 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

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing. / Jansen, Iris E.; Ye, Hui; Heetveld, Sasja; Lechler, Marie C.; Michels, Helen; Seinstra, Renée I.; Lubbe, Steven; Drouet, Valérie; Lesage, Suzanne; Majounie, Elisa; Gibbs, J. Raphael; Nalls, Mike A.; Ryten, Mina; Botia, Juan A.; Vandrovcova, Jana; Simon-Sanchez, Javier; Castillo-Lizardo, Melissa; Rizzu, Patrizia; Blauwendraat, Cornelis; Chouhan, Amit K.; Li, Yarong; Yogi, Puja; Amin, Najaf; van Duijn, Cornelia M.; Morris, Huw R.; Brice, Alexis; Singleton, Andrew B.; David, Della C.; Nollen, Ellen A.; Jain, Shushant; Shulman, Joshua M.; Heutink, Peter; International Parkinson's Disease Genetics Consortium (IPGDC).

In: Genome Biology, Vol. 18, No. 1, 22, 30.01.2017.

Research output: Contribution to journalArticleAcademicpeer-review

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

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 - Berendse, Henk W.

AU - van Dijk, Karin D.

AU - Bochdanovits, Zoltan

AU - International Parkinson's Disease Genetics Consortium (IPGDC)

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

UR - http://www.scopus.com/inward/record.url?scp=85011019247&partnerID=8YFLogxK

U2 - 10.1186/s13059-017-1147-9

DO - 10.1186/s13059-017-1147-9

M3 - Article

VL - 18

JO - Genome Biology

JF - Genome Biology

SN - 1465-6906

IS - 1

M1 - 22

ER -