The genetic architecture of Parkinson disease in Spain: characterizing population-specific risk, differential haplotype structures, and providing etiologic insight
Authors: Bandres-Ciga Sara , Ahmed Sarah , Sabir Marya S. , Blauwendraat Cornelis , Adarmes-Gómez Astrid D. , Bernal-Bernal Inmaculada , Toribio Marta Bonilla- , Buiza-Rueda Dolores , Carrillo Fátima , Carrión-Claro Mario , Gómez-Garre Pilar , Jesús Silvia , Labrador-Espinosa Miguel A. , Macias Daniel , Méndez-del-Barrio Carlota , Periñán-Tocino Teresa , Tejera-Parrado Cristina , Vargas-González Laura , Diez-Fairen Monica , Alvarez Ignacio , Tartari Juan Pablo , Buongiorno María Teresa , Aguilar Miquel , Gorostidi Ana , Bergareche Jesús Alberto , Mondragon Elisabet , Ruiz-Martínez Javier , Dols-Icardo Oriol , Kulisevsky Jaime , Marín-Lahoz Juan , Pagonabarraga Javier , Pascual-Sedano Berta , Ezquerra Mario , Cámara Ana , Compta Yaroslau , Fernández Manel , Fernández-Santiago Rubén , Muñoz Esteban , Tolosa Eduard , Valldeoriola Francesc , Gonzalez-Aramburu Isabel , Rodriguez Antonio Sanchez , Sierra María , Menéndez-González Manuel , Blazquez Marta , Garcia Ciara , Martin Esther Suarez-San , García-Ruiz Pedro , Martínez-Castrillo Juan Carlos , Vela-Desojo Lydia , Ruz Clara , Barrero Francisco Javier , Escamilla-Sevilla Francisco , Mínguez-Castellanos Adolfo , Cerdan Debora , Tabernero Cesar , Heredia Maria Jose Gomez , Errazquin Francisco Perez , Romero-Acebal Manolo , Feliz Cici , Lopez-Sendon Jose Luis , Mata Marina , Torres Irene Martínez , Kim Jonggeol Jeffrey , Brooks Janet , Saez-Atienzar Sara , Gibbs J Raphael , Jorda Rafael , Botia Juan A. , Bonet-Ponce Luis , Morrison Karen E , Clarke Carl , Tan Manuela , Morris Huw , Edsall Connor , Hernandez Dena , Simon-Sanchez Javier , Nalls Mike A , Scholz Sonja W. , Jimenez-Escrig Adriano , Duarte Jacinto , Vives Francisco , Duran Raquel , Hoenicka Janet , Alvarez Victoria , Infante Jon , Marti Maria José , Clarimón Jordi , de Munain Adolfo López , Pastor Pau , Mir Pablo , Singleton Andrew ,   on behalf of the International Parkinson Disease Genomics Consortium
Published: April 2019

ABSTRACTBackgroundThe 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.ObjectivesTo perform the largest Parkinson disease (PD) genome-wide association study (GWAS) restricted to a single country.MethodsWe 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.ResultsWe identified a novel population-specific GWAS signal atPARK2associated with AAO. We replicated four genome-wide independent signals associated with PD risk, includingSNCA, LRRK2, KANSL1/MAPTandHLA-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.ConclusionsOur 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 toPARK2as a major hallmark of PD etiology in Spain.