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The genetic architecture of Parkinson disease in Spain: characterizing population-specific risk, differential haplotype structures, and providing etiologic insight

By Sara Bandres Ciga, Sarah Ahmed, Marya S. Sabir, Cornelis Blauwendraat, Astrid D. Adarmes-Gómez, Inmaculada Bernal-Bernal, Marta Bonilla- Toribio, Dolores Buiza-Rueda, Fátima Carrillo, Mario Carrión-Claro, Pilar Gómez-Garre, Silvia Jesús, Miguel A. Labrador-Espinosa, Daniel Macias, Carlota Méndez-del-Barrio, Teresa Periñán-Tocino, Cristina Tejera-Parrado, Laura Vargas-González, Monica Diez-Fairen, Ignacio Alvarez, Juan Pablo Tartari, María Teresa Buongiorno, Miquel Aguilar, Ana Gorostidi, Jesús Alberto Bergareche, Elisabet Mondragon, Javier Ruiz-Martínez, Oriol Dols-Icardo, Jaime Kulisevsky, Juan Marín-Lahoz, Javier Pagonabarraga, Berta Pascual-Sedano, Mario Ezquerra, Ana Cámara, Yaroslau Compta, Manel Fernández, Rubén Fernández-Santiago, Esteban Muñoz, Eduard Tolosa, Francesc Valldeoriola, Isabel Gonzalez-Aramburu, Antonio Sanchez Rodriguez, María Sierra, Manuel Menéndez-González, Marta Blazquez, Ciara Garcia, Esther Suarez-San Martin, Pedro García-Ruiz, Juan Carlos Martínez-Castrillo, Lydia Vela-Desojo, Clara Ruz, Francisco Javier Barrero, Francisco Escamilla-Sevilla, Adolfo Mínguez-Castellanos, Debora Cerdan, Cesar Tabernero, Maria Jose Gomez Heredia, Francisco Perez Errazquin, Manolo Romero-Acebal, Cici Feliz, Jose Luis Lopez-Sendon, Marina Mata, Irene Martínez Torres, Jonggeol Jeffrey Kim, Janet Brooks, Sara Saez-Atienzar, J Raphel Gibbs, Rafael Jorda, Juan A. Botia, Luis Bonet-Ponce, Karen E. Morrison, Carl Clarke, Manuela Tan, Huw Morris, Connor Edsall, Dena Hernandez, Javier Simon-Sanchez, Mike A Nalls, Sonja W. Scholz, Adriano Jimenez-Escrig, Jacinto Duarte, Francisco Vives, Raquel Duran, Janet Hoenicka, Victoria Alvarez, Jon Infante, Maria José Marti, Jordi Clarimón, Adolfo López de Munain, Pau Pastor, Pablo Mir, Andrew Singleton, on behalf of the International Parkinson Disease Genomics Consortium

Posted 18 Apr 2019
bioRxiv DOI: 10.1101/609016 (published DOI: 10.1002/mds.27864)

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 Parkinson disease (PD) genome-wide association study (GWAS) restricted to a single country. Methods: We performed a GWAS for both risk of PD and age at onset (AAO) 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 GWAS signal at PARK2 associated with AAO. 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 via two-sample Mendelian randomization in expression and methylation datasets. 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.

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