The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight. Bandres-Ciga, Sara Sarah, Ahmed Marya S., Sabir 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. Macías, 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, Miguel 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, Estaban Tolosa, Eduard Valldeoriola, Francesc Gonzalez-Aramburu, Isabel Sanchez Rodriguez, Antonio Sierra, Maria Menéndez-González, Manuel Blazquez, Marta García, Ciara Suarez-San Martin, Esther García-Ruiz, Pedro Martínez-Castrillo, Juan Carlos Vela-Desojo, Lydia Ruz, Clara Barrero Hernández, Francisco Javier Escamilla-Sevilla, Francisco Mínguez-Castellanos, Adolfo Cerdan, Debora Tabernero, Cesar Gómez Heredia, Maria José Pérez Errazquin, Francisco Romero Acebal, Manuel Feliz, Cici Lopez-Sendon, Jose Luis Mata, Marina Martínez Torres, Irene Kim, Jonggeol Jeffrey Dalgard, Clifton L Brooks, Janet Saez- SaezAtienzar, 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 Simón-Sanchez, Javier Nalls, Mike A Scholz, Sonja W Jimenez-Escrig, Adriano Duarte, Jacinto Vives Montero, Francisco Durán Ogalla, Raquel Hoenicka, Janet Álvarez, Victoria Infante, Jon Marti, Maria Jose Clarimón, Jordi Lopez De Munain, Adolfo Pastor, Pau Singleton, Andrew Age at onset Parkinson’s disease Polygenic risk score Risk haplotype Spanish population This research was supported, in part, by the Intra-mural Research Program of the National Institutes of Health (National Institute on Aging, National Institute of Neurological Disorders and Stroke; project numbers: 1ZIA NS003154-03, Z01-AG000949-02, and Z01-ES101986). In addition, this work was supported by the Department of Defense (award W81XWH-09-2-0128), The Michael J Fox Foundation for Parkinson’s Research, and the ISCIII Grants PI 15/0878 (Fondos Feder) to V.A. and PI 15/01013 to J,H. This study was supported by grants from the Spanish Ministry of Economy and Competitiveness (PI14/01823, PI16/01575, PI18/01898, [SAF2006-10126 (2006-2009), SAF2010-22329-C02-01 (2010-2012), and SAF2013-47939-R (2013-2018)]), co-founded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0437-2012, PI-0471-2013), the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the Fundación Alicia Koplowitz, and the Fundación Mutua Madrileña. Pilar Gómez-Garre was supported by the “Miguel Servet” (from ISCIII16 FEDER) and “Nicolás Monardes” (from Andalusian Ministry of Health) programmes. Silvia Jesús Maestre was supported by the “Juan Rodés” programme, and Daniel Macías-García was supported by the “Río Hortega” programme (both from ISCIII-FEDER). Cristina Tejera Parrado was supported by VPPI-US from the Universidad de Sevilla. This research has been conducted using samples from the HUVR-IBiS Biobank (Andalusian Public Health System Biobank and ISCIII-Red de Biobancos PT13/0010/0056). This work was also supported by the grant PSI2014-57643 from the Junta de Andalucía to the CTS-438 group and a research award from the Andalusian Society of Neurology. Background: 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. 2024-04-18T09:03:59Z 2024-04-18T09:03:59Z 2019-12 info:eu-repo/semantics/article Published version: Bandres-Ciga S, et al. International Parkinson Disease Genomics Consortium. The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight. Mov Disord. 2019 Dec;34(12):1851-1863. Epub 2019 Oct 29. PMID: 31660654; PMCID: PMC8393828. doi: 10.1002/mds.27864 https://hdl.handle.net/10481/90874 10.1002/mds.27864 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess Attribution-NonCommercial-NoDerivatives 4.0 Internacional Wiley