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; International Parkinson’s Disease Genetics Consortium (IPGDC)

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, International Parkinson’s Disease Genetics Consortium (IPGDC)

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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 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.

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

Keywords

Parkinson's disease
Genomics
Whole-exome sequencing
Loss-of-function
Rare variants
Functional screening
Mitochondria
Parkin
alpha-synuclein
Animal model
RECEPTOR TYROSINE PHOSPHATASE
DOMAIN-CONTAINING 2
ALPHA-SYNUCLEIN
DROSOPHILA MODEL
CAENORHABDITIS-ELEGANS
G-PATCH
ALZHEIMERS-DISEASE
RETROMER COMPLEX
NETWORK ANALYSIS
AXON GUIDANCE

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Additional file 1: of Discovery and functional prioritization of Parkinson’s disease candidate genes from large-scale whole exome sequencing
Jansen, I. E. (Contributor), Ye, H. (Contributor), Michels, H. (Contributor), Seinstra, R. (Contributor), Lubbe, S. (Contributor), Drouet, V. (Contributor), Lesage, S. (Contributor), Majounie, E. (Contributor), Gibbs, J. R. (Contributor), Nalls, M. A. (Contributor), Ryten, M. (Contributor), Botia, J. A. (Contributor), Vandrovcova, J. (Contributor), Simon-Sanchez, J. (Contributor), Castillo-Lizardo, M. (Contributor), Heetveld, S. (Contributor), Lechler, M. C. (Contributor), Rizzu, P. (Contributor), Blauwendraat, C. (Contributor), Chouhan, A. K. (Contributor), Li, Y. (Contributor), Yogi, P. (Contributor), Amin, N. (Contributor), van Duijn, C. M. (Contributor), Morris, H. R. (Contributor), Brice, A. (Contributor), Singleton, A. B. (Contributor), David, D. C. (Contributor), Nollen, E. A. (Contributor), Jain, S. (Contributor), Shulman, J. M. (Contributor) & Heutink, P. (Contributor), figshare Academic Research System, 30-Jan-2017
DOI: 10.6084/m9.figshare.c.3677803_d2.v1
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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., ... 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(22). https://doi.org/10.1186/s13059-017-1147-9

@article{ca425ef402af489dacf917b8ea9deefa,

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 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.",

keywords = "Parkinson's disease, Genomics, Whole-exome sequencing, Loss-of-function, Rare variants, Functional screening, Mitochondria, Parkin, alpha-synuclein, Animal model, RECEPTOR TYROSINE PHOSPHATASE, DOMAIN-CONTAINING 2, ALPHA-SYNUCLEIN, DROSOPHILA MODEL, CAENORHABDITIS-ELEGANS, G-PATCH, ALZHEIMERS-DISEASE, RETROMER COMPLEX, NETWORK ANALYSIS, AXON GUIDANCE",

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 {International Parkinson{\textquoteright}s Disease Genetics Consortium (IPGDC)}",

year = "2017",

month = jan,

day = "30",

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

language = "English",

volume = "18",

journal = "Genome Biology",

issn = "1465-6906",

publisher = "BMC",

number = "22",

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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 & 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. 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 - 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 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.

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 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.

KW - Parkinson's disease

KW - Genomics

KW - Whole-exome sequencing

KW - Loss-of-function

KW - Rare variants

KW - Functional screening

KW - Mitochondria

KW - Parkin

KW - alpha-synuclein

KW - Animal model

KW - RECEPTOR TYROSINE PHOSPHATASE

KW - DOMAIN-CONTAINING 2

KW - ALPHA-SYNUCLEIN

KW - DROSOPHILA MODEL

KW - CAENORHABDITIS-ELEGANS

KW - G-PATCH

KW - ALZHEIMERS-DISEASE

KW - RETROMER COMPLEX

KW - NETWORK ANALYSIS

KW - AXON GUIDANCE

U2 - 10.1186/s13059-017-1147-9

DO - 10.1186/s13059-017-1147-9

M3 - Article

C2 - 28137300

SN - 1465-6906

VL - 18

JO - Genome Biology

JF - Genome Biology

IS - 22

ER -

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

Abstract

Keywords

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Additional file 1: of Discovery and functional prioritization of Parkinson’s disease candidate genes from large-scale whole exome sequencing

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