@misc{10481/90874,
year = {2019},
month = {12},
url = {https://hdl.handle.net/10481/90874},
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 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.},
organization = {National Institutes of Health  1ZIA NS003154-03, Z01-AG000949-02, Z01-ES101986},
organization = {Department of Defense (award W81XWH-09-2-0128)},
organization = {Foundation for Parkinson’s Research},
organization = {ISCIII Grants PI 15/0878 (Fondos Feder), PI 15/01013},
organization = {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)])},
organization = {Sociedad Andaluza de Neurología},
organization = {Jacques and Gloria Gossweiler Foundation},
organization = {Fundación Alicia Koplowitz},
organization = {Fundación Mutua Madrileña},
organization = {ISCIII16 FEDER},
organization = {ISCIII-FEDER},
organization = {Universidad de Sevilla},
organization = {ISCIII-Red de Biobancos PT13/0010/0056},
organization = {Junta de Andalucía (CVI-02526, CTS-7685), (PI-0437-2012, PI-0471-2013, PSI2014-57643)},
organization = {Andalusian Society of Neurology CTS-438},
publisher = {Wiley},
keywords = {Age at onset},
keywords = {Parkinson’s disease},
keywords = {Polygenic risk score},
keywords = {Risk haplotype},
keywords = {Spanish population},
title = {The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight.},
doi = {10.1002/mds.27864},
author = {Bandres-Ciga, Sara and Sarah, Ahmed and Marya S., Sabir and Blauwendraat, Cornelis and Adarmes-Gómez, Astrid D and Bernal-Bernal, Inmaculada and Bonilla-Toribio, Marta and Buiza-Rueda, Dolores and Carrillo, Fátima and Carrión-Claro, Mario and Gómez Garre, Pilar and Jesús, Silvia and Labrador-Espinosa, Miguel A. and Macías, Daniel and Méndez-del-Barrio, Carlota and Periñán-Tocino, Teresa and Tejera-Parrado, Cristina and Vargas González, Laura and Diez-Fairen, Monica and Alvarez, Ignacio and Tartari, Juan Pablo and Buongiorno, Mariateresa and Aguilar, Miguel and Gorostidi, Ana and Bergareche, Jesús Alberto and Mondragon, Elisabet and Vinagre-Aragon, Ana and Croitoru, Ioana and Ruiz-Martínez, Javier and Dols-Icardo, Oriol and Kulisevsky, Jaime and Marín-Lahoz, Juan and Pagonabarraga, Javier and Pascual-Sedano, Berta and Ezquerra, Mario and Cámara, Ana and Compta, Yaroslau and Fernández, Manel and Fernández-Santiago, Rubén and Muñoz, Estaban and Tolosa, Eduard and Valldeoriola, Francesc and Gonzalez-Aramburu, Isabel and Sanchez Rodriguez, Antonio and Sierra, Maria and Menéndez-González, Manuel and Blazquez, Marta and García, Ciara and Suarez-San Martin, Esther and García-Ruiz, Pedro and Martínez-Castrillo, Juan Carlos and Vela-Desojo, Lydia and Ruz, Clara and Barrero Hernández, Francisco Javier and Escamilla-Sevilla, Francisco and Mínguez-Castellanos, Adolfo and Cerdan, Debora and Tabernero, Cesar and Gómez Heredia, Maria José and Pérez Errazquin, Francisco and Romero Acebal, Manuel and Feliz, Cici and Lopez-Sendon, Jose Luis and Mata, Marina and Martínez Torres, Irene and Kim, Jonggeol  Jeffrey and Dalgard, Clifton L and Brooks, Janet and Saez- SaezAtienzar, Sara and Gibbs, J. Raphael and Jorda, Rafael and Botia, Juan A and Bonet-Ponce, Luis and Morrison, Karen E and Clarke, Carl and Tan, Manuela and Morris, Huw and Edsall, Connor and Hernandez, Dena and Simón-Sanchez, Javier and Nalls, Mike A and Scholz, Sonja W and Jimenez-Escrig, Adriano and Duarte, Jacinto and Vives Montero, Francisco and Durán Ogalla, Raquel and Hoenicka, Janet and Álvarez, Victoria and Infante, Jon and Marti, Maria Jose and Clarimón, Jordi and Lopez De Munain, Adolfo and Pastor, Pau and Singleton, Andrew},
}