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Title: The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight.
Bandres-Ciga, Sara
Ahmed, Sarah
Sabir, Marya S
Blauwendraat, Cornelis
Adarmes-Gómez, Astrid D
Bernal-Bernal, Inmaculada
Bonilla-Toribio, Marta
Buiza-Rueda, Dolores
Carrillo, Fátima
Carrión-Claro, Mario
Gómez-Garre, Pilar
Jesús, Silvia
Labrador-Espinosa, Miguel A
Macias, Daniel
Méndez-Del-Barrio, Carlota
Periñán-Tocino, Teresa
Tejera-Parrado, Cristina
Vargas-González, Laura
Diez-Fairen, Monica
Alvarez, Ignacio
Tartari, Juan Pablo
Buongiorno, Mariateresa
Aguilar, Miquel
Gorostidi, Ana
Bergareche, Jesús Alberto
Mondragon, Elisabet
Vinagre-Aragon, Ana
Croitoru, Ioana
Ruiz-Martínez, Javier
Dols-Icardo, Oriol
Kulisevsky, Jaime
Marín-Lahoz, Juan
Pagonabarraga, Javier
Pascual-Sedano, Berta
Ezquerra, Mario
Cámara, Ana
Compta, Yaroslau
Fernández, Manel
Fernández-Santiago, Rubén
Muñoz, Esteban
Tolosa, Eduard
Valldeoriola, Francesc
Gonzalez-Aramburu, Isabel
Sanchez Rodriguez, Antonio
Sierra, María
Menéndez-González, Manuel
Blazquez, Marta
Garcia, Ciara
Suarez-San Martin, Esther
García-Ruiz, Pedro
Martínez-Castrillo, Juan Carlos
Vela-Desojo, Lydia
Ruz, Clara
Barrero, Francisco Javier
Escamilla-Sevilla, Francisco
Mínguez-Castellanos, Adolfo
Cerdan, Debora
Tabernero, Cesar
Gomez Heredia, Maria Jose
Perez Errazquin, Francisco
Romero-Acebal, Manolo
Feliz, Cici
Lopez-Sendon, Jose Luis
Mata, Marina
Martínez Torres, Irene
Kim, Jonggeol Jeffrey
Dalgard, Clifton L
American Genome Center
Brooks, Janet
Saez-Atienzar, Sara
Gibbs, J Raphael
Jorda, Rafael
Botia, Juan A
Bonet-Ponce, Luis
Morrison, Karen E
Clarke, Carl
Tan, Manuela
Morris, Huw
Edsall, Connor
Hernandez, Dena
Simon-Sanchez, Javier
Nalls, Mike A
Scholz, Sonja W
Jimenez-Escrig, Adriano
Duarte, Jacinto
Vives, Francisco
Duran, Raquel
Hoenicka, Janet
Alvarez, Victoria
Infante, Jon
Marti, Maria José
Clarimón, Jordi
López de Munain, Adolfo
Pastor, Pau
Mir, Pablo
Singleton, Andrew
International Parkinson Disease Genomics Consortium
Issue Date: 29-Oct-2019
Citation: Mov Disord.2019;(34)12:1851-1863
Abstract: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. To perform the largest PD genome-wide association study restricted to a single country. We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society.
PMID: 31660654
Rights: openAccess
Appears in Collections:Fundaciones e Institutos de Investigación > FIIB H. U. Infanta Sofía y H. U. Henares > Artículos

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