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

作者：Demis A. Kia, David Zhang, Sebastian Guelfi, Claudia Manzoni, Leon Hubbard, Regina H. Reynolds, Juan A. Botía, Mina Ryten, Raffaele Ferrari, Patrick A. Lewis, Nigel Williams, Daniah Trabzuni, John Hardy, Nicholas Wood, Alastair J. Noyce, Rauan Kaiyrzhanov, Ben Middlehurst, Demis A. Kia, Manuela Tan, Henry Houlden, Huw R. Morris, Hélène Plun‐Favreau, Peter Holmans, John Hardy, Daniah Trabzuni, José Brás, John P. Quinn, Kin Y. Mok, Kerri J. Kinghorn, Kimberley J. Billingsley, Nicholas Wood, Patrick A. Lewis, Sebastian R. Schreglmann, Rita Guerreiro, Ruth C. 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, María Martínez, Claudia Schulte, Kathrin Brockmann, Javier Simón‐Sánchez, Peter Heutink, Patrizia Rizzu, Manu Sharma, Thomas Gasser, Aude Nicolas, Mark Cookson, Sara Bandrés‐Ciga, Cornelis Blauwendraat, David W. Craig, Faraz Faghri, J. Raphael Gibbs, Dena Hernández, Kendall Van Keuren‐Jensen, Joshua Shulman, Hampton L. Leonard, Mike A. Nalls, Laurie Robak, Steven Lubbe, Steven Finkbeiner, Niccolò E. Mencacci, Codrin Lungu, Andrew Singleton, Sonja W. Scholz, Xylena Reed, Roy N. Alcalay, Ziv Gan‐Or, Guy A. Rouleau, Lynne Krohn, Jacobus J. van Hilten, Johan Marinus, Astrid Adarmes‐Gómez, Miquel Aguilar, Ignacio Álvarez, Victoria Álvarez, Francisco Javier Barrero, Jesús Alberto Bergareche Yarza, Inmaculada Bernal‐Bernal, Marta Blázquez Estrada, Marta Bonilla‐Toribio, Juan A. Botía, María Teresa Boungiorno, Dolores Buiza‐Rueda, Anna Maria Novella Càmara, Fátima Carrillo, Mario Carrión‐Claro, Debora Cerdan, Jordi Clarimón, Yaroslau Compta, Mónica Díez-Fairén, Oriol Dols‐Icardo, J. Duarte, Raquel Durán, Francisco Escamilla‐Sevilla, Mario Ezquerra, Cici Feliz, Manel Fernández, Rubén Fernández‐Santiago, Ciara García, Pedro Ruiz, Pilar Gómez‐Garre, María José Gómez Heredia, Isabel González Aramburu, Ana Gorostidi Pagola, Janet Hoenicka, Jon Infante, Adriano Jiménez‐Escrig, Jaime Kulisevsky, Miguel A. Labrador‐Espinosa, José Luis López-Sendón, Adolfo López de Munaín Arregui, Daniel Macías, Irene Martínez‐Torres, Juan Marín‐Lahoz, Marı́a José Martı́, Juan Carlos Martínez‐Castrillo, Carlota Méndez‐del‐Barrio, Manuel Menéndez‐González, Marina Mata Adolfo Mínguez, Pablo Mir, Elisabet Mondragón Rezola, Esteban Muñoz, Javier Pagonabarraga, Pau Pástor, Francisco Pérez Errazquin, María Teresa Periñán, Javier Ruiz‐Martínez, Clara Ruz, A Rodríguez, María Sierra, Esther Suárez-Sanmartín, César Tabernero, Juan Pablo Tartari, Cristina Tejera‐Parrado, Eduard Tolosa, Francesc Valldeoriola, Laura Vargas‐González, Lydia Vela, Francisco Vives, Alexander Zimprich, Lasse Pihlstrøm, Mathias Toft, Sulev Kõks, Pille Taba, Sharon Hassin‐Baer, Michael E. Weale, Adaikalavan Ramasamy, Colin Smith, Manuel Sebastian Guelfi, Karishma D’Sa, Paola Forabosco, Juan A. Botía · 发表于：JAMA Neurology · 年份：2021 · DOI：10.1001/jamaneurol.2020.5257 · 被引用次数：211 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Genetic Associations and Epidemiology、Nuclear Receptors and Signaling

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 [O...