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

bioRxiv (Cold Spring Harbor Laboratory)2019

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Sara Bandrés‐Ciga, Sarah Ahmed, Marya S. Sabir, Cornelis Blauwendraat, Astrid 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 Macías, Carlota Méndez‐del‐Barrio, María Teresa Periñán, Cristina Tejera‐Parrado, Laura Vargas‐González, Mónica Díez-Fairén, Ignacio Álvarez, Juan Pablo Tartari, Maríateresa Buongiorno, Miquel Aguilar, Ana Gorostidi, J Bergareche, Elisabet Mondragón, 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 González Aramburu, A Rodríguez, María Sierra, Manuel Menéndez‐González, Marta Blázquez Estrada, Ciara García, Esther Suarez‐San Martin, Pedro Ruiz, Juan Carlos Martínez‐Castrillo, Lydia Vela, Clara Ruz, Francisco Javier Barrero, Francisco Escamilla‐Sevilla, Adolfo Mínguez‐Castellanos, Debora Cerdan, César Tabernero, María José Gómez Heredia, Francisco Pérez Errazquin, Manolo Romero‐Acebal, Cici Feliz, José Luis López-Sendón, Marina Mata, Irene Martínez‐Torres, Jonggeol Jeffrey Kim, Janet Brooks, Sara Sáez-Atiénzar, J. Raphael Gibbs, Rafael Jorda, Juan A. Botía, Luis Bonet‐Ponce, Karen Morrison, Carl E Clarke, Manuela Tan, Huw R. Morris, Connor Edsall, Dena Hernández, Javier Simón‐Sánchez, Mike A. Nalls, Sonja W. Scholz, Adriano Jiménez‐Escrig, J. Duarte, Francisco Vives, Raquel Durán, Janet Hoenicka, Victoria Álvarez, Jon Infante, Marı́a José Martı́, Jordi Clarimón, Adolfo López de Munain, Pau Pástor, Pablo Mir, Andrew Singleton

Abstract

ABSTRACT 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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Abstract

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