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Title

The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight

AuthorsBandres-Ciga, Sara; Ahmed, Sarah; Sabir, Marya S.; Blauwendraat, Cornelis; Adarmes Gómez, A. D.; Bernal-Bernal, Inmaculada; Bonilla-Toribio, Marta; Buiza-Rueda, Dolores; Carrillo, Fátima; Carrión-Claro, Mario; Gómez-Garre, Pilar; Jesús Maestre, Silvia; Labrador, Miguel Ángel; Macías García, Daniel; Méndez-Del Barrio, Carlota; Perinán, María Teresa; Tejera-Parrado, Cristina; Vargas-González, Laura; Díez-Fairen, M.; Álvarez, Ignacio CSIC; Tartari, J. P.; Buongiorno, Maria Teresa; 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-Mora, Javier; Pascual-Sedano, B.; Ezquerra, Mario; Cámara, Ana; Compta, Yaroslau; Fernandez, Manel CSIC ORCID ; Fernández-Santiago, Rubén; Muñoz, Esteban; Tolosa, Eduardo; Valldeoriola, Francesc; González-Aramburu, Isabel; Sanchez Rodriguez, Antonio; Sierra, María; Menéndez González, M.; Blazquez, Marta; Garcia, Ciara; Suarez-San Martin, Esther; García-Ruíz, Pedro; Martínez-Castrillo, J. C.; Vela-Desojo, Lydia; Ruz, Clara; Barrero, Francisco Javier; Escamilla-Sevilla, Francisco; Mínguez-Castellanos, Adolfo; Cerdan, Debora; Tabernero, César; Gomez Heredia, Maria Jose; Perez Errazquin, Francisco; Romero-Acebal, Manolo; Feliz, Cici; Lopez-Sendon, José Luis; Mata, Marina; Martínez Torres, Irene; Kim, Jonggeol Jeffrey; Dalgard, Clifton L.; 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; Hernández, Dena; Simón-Sánchez, Javier CSIC; Nalls, Michael A.; Scholz, Sonja; Jiménez Escrig, Adriano; Duarte, Jacinto; Vives, Francisco; Duran, Raquel; Hoenicka, Janet; Álvarez, Victoria; Infante, Jon; Martí, María-José; Clarimón, Jordi; López de Munain, Adolfo; Pastor, Pau; Mir, Pablo CSIC ORCID; Singleton, Andrew B.
KeywordsAge at onset
Parkinson's disease
Polygenic
Risk score risk haplotype
Spanish population
Issue DateDec-2019
PublisherJohn Wiley & Sons
CitationMovement Disorders 34(12): 1851-1863 (2019)
AbstractBackground: 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. Objectives: To perform the largest PD genome-wide association study restricted to a single country. Methods: 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. Results: 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. Conclusions: 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.
Publisher version (URL)http://dx.doi.org/10.1002/mds.27864
URIhttp://hdl.handle.net/10261/205254
DOIhttp://dx.doi.org/10.1002/mds.27864
Identifiersdoi: 10.1002/mds.27864
e-issn: 1531-8257
issn: 0885-3185
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