Demis A. Kia
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
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 |
Files
Jamaneurology Kia 2021 Oi 200099 1617209045.71518
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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/
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