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

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 sin...

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Published in:Movement disorders 2019-12, Vol.34 (12), p.1851-1863
Main Authors: Ahmed, Sarah, Jesús, Silvia, Méndez‐del‐Barrio, Carlota, Vargas‐González, Laura, Tartari, Juan Pablo, Mondragon, Elisabet, Vinagre‐Aragon, Ana, Dols‐Icardo, Oriol, Pascual‐Sedano, Berta, Ezquerra, Mario, Cámara, Ana, Compta, Yaroslau, Fernández, Manel, Sierra, María, Menéndez‐González, Manuel, García‐Ruiz, Pedro, Vela‐Desojo, Lydia, Barrero, Francisco Javier, Mínguez‐Castellanos, Adolfo, Cerdan, Debora, Gomez Heredia, Maria Jose, Feliz, Cici, Lopez‐Sendon, Jose Luis, Martínez Torres, Irene, Kim, Jonggeol Jeffrey, Botia, Juan A., Morrison, Karen E., Morris, Huw, Edsall, Connor, Vives, Francisco, Duran, Raquel, Hoenicka, Janet, Alvarez, Victoria, Marti, Maria José, Singleton, Andrew, Noyce, Alastair J, Holmans, Peter, Trabzuni, Daniah, Bras, Jose, Wood, Nicholas W, Guerreiro, Rita, Guelfi, Sebastian, Chelban, Viorica, Foltynie, Thomas, Brockmann, Kathrin, Gasser, Thomas, Cookson, Mark R, Blauwendraat, Cornelis, Craig, David W., Faghri, Faraz, Gibbs, J Raphael, Shulman, Joshua M., Leonard, Hampton L., Nalls, Mike A., Robak, Laurie, Lubbe, Steven, Mencacci, Niccolo E., Alcalay, Roy N., Krohn, Lynne, Aguilar, Miquel, Alvarez, Ignacio, Yarza, Jesús Alberto Bergareche, Blazquez, Marta, Botía, Juan A., Boungiorno, María Teresa, Buiza-Rueda, Dolores, Clarimón, Jordi, Casa, Beatríz, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Heredia, Maria Jose Gomez, Infante, Jon, Jimenez-Escrig, Adriano, Arregui, Adolfo López de Munain, Marín, Juan, Mata, Marina, Mínguez, Adolfo, Mir, Pablo, Pascual-Sedano, Berta, Pastor, Pau, Errazquin, Francisco Perez, Ruiz-Martínez, Javier, Rodriguez, Antonio Sanchez, Suarez-Sanmartin, Esther, Tolosa, Eduard, Valldeoriola, Francesc, Vargas-González, Laura, Zimprich, Alexander, Taba, Pille, Dalgard, Clifton L., Adeleye, Adelani, Soltis, Anthony R., Bacikova, Dagmar, Wilkerson, Matthew D.
Format: Article
Language:English
Subjects:
Adult
age at onset
Age of Onset
Aged
Aged, 80 and over
Case-Control Studies
Chromosome Mapping
Cost of Illness
DNA Methylation
Etiology
Female
Gene mapping
Genetic analysis
Genetic Predisposition to Disease - genetics
Genome-wide association studies
Genome-Wide Association Study
Genomes
Genotype
Haplotypes
Heritability
Histocompatibility antigen HLA
Humans
Learning algorithms
LRRK2 protein
Machine Learning
Male
Middle Aged
Movement disorders
Multifactorial Inheritance
Neurodegenerative diseases
Parkinson Disease - genetics
Parkinson's disease
polygenic risk score
Population
Population genetics
risk haplotype
Spain
Spanish population
Ubiquitin-Protein Ligases - genetics
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Description
Summary: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. © 2019 International Parkinson and Movement Disorder Society
ISSN:0885-3185
1531-8257
DOI:10.1002/mds.27864