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Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets

Kia, Demis A.; Zhang, David; Guelfi, Sebastian; Manzoni, Claudia; Hubbard, Leon; Reynolds, Regina H.; Botía, Juan; Ryten, Mina; Ferrari, Raffaele; Lewis, Patrick A.; Williams, Nigel; Trabzuni, Daniah; Hardy, John; Wood, Nicholas W.; Noyce, Alastair J.; Kaiyrzhanov, Rauan; Middlehurst, Ben; Kia, Demis A.; Tan, Manuela; Houlden, Henry; Morris, Huw R.; Plun-Favreau, Helene; Holmans, Peter; Hardy, John; Trabzuni, Daniah; Bras, Jose; PhD, John Quinn; Mok, Kin Y.; Kinghorn, Kerri J.; Billingsley, Kimberley; Wood, Nicholas W.; Lewis, Patrick; Schreglmann, Sebastian; Guerreiro, Rita; Lovering, Ruth; R'Bibo, Lea; Manzoni, Claudia; Rizig, Mie; Ryten, Mina; Guelfi, Sebastian; Escott-Price, Valentina; Chelban, Viorica; Foltynie, Thomas; Williams, Nigel; Brice, Alexis; Danjou, Fabrice; Lesage, Suzanne; Corvol, Jean-Christophe; Martinez, Maria; Schulte, Claudia; Brockmann, Kathrin; Simón-Sánchez, Javier; Heutink, Peter; Rizzu, Patrizia; Sharma, Manu; Gasser, Thomas; Nicolas, Aude; Cookson, Mark R.;...

Authors

Demis A. Kia

David Zhang

Sebastian Guelfi

Claudia Manzoni

Leon Hubbard

Regina H. Reynolds

Juan Botía

Mina Ryten

Raffaele Ferrari

Patrick A. Lewis

Nigel Williams

Daniah Trabzuni

John Hardy

Nicholas W. Wood

Alastair J. Noyce

Rauan Kaiyrzhanov

Ben Middlehurst

Demis A. Kia

Manuela Tan

Henry Houlden

Huw R. Morris

Helene Plun-Favreau

Peter Holmans

John Hardy

Daniah Trabzuni

Jose Bras

John Quinn PhD

Kin Y. Mok

Kerri J. Kinghorn

Kimberley Billingsley

Nicholas W. Wood

Patrick Lewis

Sebastian Schreglmann

Rita Guerreiro

Ruth Lovering

Lea R'Bibo

Claudia Manzoni

Mie Rizig

Mina Ryten

Sebastian Guelfi

Valentina Escott-Price

Viorica Chelban

Thomas Foltynie

Nigel Williams

Alexis Brice

Fabrice Danjou

Suzanne Lesage

Jean-Christophe Corvol

Maria Martinez

Claudia Schulte

Kathrin Brockmann

Javier Simón-Sánchez

Peter Heutink

Patrizia Rizzu

Manu Sharma

Thomas Gasser

Aude Nicolas

Mark R. Cookson

Sara Bandres-Ciga

Cornelis Blauwendraat

David W. Craig

Faraz Faghri

J. Raphael Gibbs

Dena G. Hernandez

Kendall Van Keuren-Jensen

Joshua M. Shulman

Hampton L. Leonard

Mike A. Nalls

Laurie Robak

Steven Lubbe

Steven Finkbeiner

Niccolo E. Mencacci

Codrin Lungu

Andrew B Singleton

Sonja W. Scholz

Xylena Reed

Roy N. Alcalay

Ziv Gan-Or

Guy A. Rouleau

Lynne Krohn

Jacobus J. van Hilten

Johan Marinus

Astrid D. Adarmes-Gómez

Miquel Aguilar

Ignacio Alvarez

Victoria Alvarez

Francisco Javier Barrero

Jesús A. Bergareche Yarza

Inmaculada Bernal-Bernal

Marta Blazquez

Marta Bonilla-Toribio

Juan A. Botía

María T. Boungiorno

Dolores Buiza-Rueda

Ana Càmara

Fátima Carrillo

Mario Carrión-Claro

Debora Cerdan

Jordi Clarimón

Yaroslau Compta

Monica Diez-Fairen

Oriol Dols-Icardo

Jacinto Duarte

Raquel Duran

Francisco Escamilla-Sevilla

Mario Ezquerra

Cici Feliz

Manel Fernàndez

Rubén Fernàndez-Santiago

Ciara Garcia

Pedro García-Ruiz

Pilar Gómez-Garre

Maria J. Gomez Heredia

Isabel Gonzalez-Aramburu

Ana G. Pagola

Janet Hoenicka

Jon Infante

Adriano Jimenez-Escrig

Jaime Kulisevsky

Miguel A. Labrador-Espinosa

Jose Luis Lopez-Sendon

Adolfo López de Munain Arregui

Daniel Macias

Irene Martínez Torres

Juan Marín

Maria Jose Marti

Juan Carlos Martínez-Castrillo

Carlota Mèndez-del-Barrio

Manuel Menéndez González

Marina Mata Adolfo Mínguez

Pablo Mir

Elisabet Mondragon Rezola

Esteban Muñoz

Javier Pagonabarraga

Pau Pastor

Francisco Perez Errazquin

Teresa Perinán-Tocino

Javier Ruiz-Martínez

Clara Ruz

Antonio Sanchez Rodriguez

María Sierra

Esther Suarez-Sanmartin

Cesar Tabernero

Juan Pablo Tartari

Cristina Tejera-Parrado

Eduard Tolosa

Francesc Valldeoriola

Laura Vargas-González

Lydia Vela

Francisco Vives

Alexander Zimprich

Lasse Pihlstrom

Mathias Toft

Sulev Koks

Pille Taba

Sharon Hassin-Baer

Michael Weale

Adaikalavan Ramasamy

Colin Smith

Manuel Sebastian Guelfi

Karishma D'sa

Paola Forabosco

Juan A. Botiá

United Kingdom Brain Expression Consortium (UKBEC) and the International Parkinson’s Disease Genomics Consortium (IPDGC)



Contributors

Patrick Lewis
Researcher

Abstract

IMPORTANCE Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD.
OBJECTIVE To investigate what genes and genomic processes underlie the risk of sporadic PD.
DESIGN AND SETTING This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks.
MAIN OUTCOMES AND MEASURES It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role.
RESULTS Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance.
CONCLUSIONS AND RELEVANCE Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies.

Citation

Kia, D. A., Zhang, D., Guelfi, S., Manzoni, C., Hubbard, L., Reynolds, R. H., Botía, J., Ryten, M., Ferrari, R., Lewis, P. A., Williams, N., Trabzuni, D., Hardy, J., Wood, N. W., Noyce, A. J., Kaiyrzhanov, R., Middlehurst, B., Kia, D. A., Tan, M., Houlden, H., …United Kingdom Brain Expression Consortium (UKBEC) and the International Parkinson’s Disease Genomics Consortium (IPDGC). (2021). Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets. JAMA Neurology, 78(4), 464. https://doi.org/10.1001/jamaneurol.2020.5257

Journal Article Type Article
Acceptance Date Sep 11, 2020
Online Publication Date Feb 1, 2021
Publication Date Apr 1, 2021
Deposit Date Jul 9, 2021
Publicly Available Date Jul 14, 2021
Journal JAMA Neurology
Print ISSN 2168-6149
Electronic ISSN 2168-6157
Publisher American Medical Association
Peer Reviewed Peer Reviewed
Volume 78
Issue 4
Pages 464
DOI https://doi.org/10.1001/jamaneurol.2020.5257
Keywords Clinical Neurology
Public URL https://rvc-repository.worktribe.com/output/1549863

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