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

Authors:
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 Mariateresa Buongiorno Miquel Aguilar Ana Gorostidi Jesús Alberto Bergareche Elisabet Mondragon Ana Vinagre-Aragon Ioana Croitoru 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 Clifton L Dalgard Janet Brooks Sara Saez-Atienzar J Raphael 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

Mov Disord 2019 12 29;34(12):1851-1863. Epub 2019 Oct 29.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

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.

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Source
http://dx.doi.org/10.1002/mds.27864DOI Listing
December 2019
5.680 Impact Factor

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