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 , Bonilla‐Toribio Marta , 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 Mariateresa , Aguilar Miquel , Gorostidi Ana , Bergareche Jesús Alberto , Mondragon Elisabet , Vinagre‐Aragon Ana , Croitoru Ioana , 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 , Sanchez Rodriguez Antonio , Sierra María , Menéndez‐González Manuel , Blazquez Marta , Garcia Ciara , Suarez‐San Martin Esther , 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 , Gomez Heredia Maria Jose , Perez Errazquin Francisco , Romero‐Acebal Manolo , Feliz Cici , Lopez‐Sendon Jose Luis , Mata Marina , Martínez Torres Irene , Kim Jonggeol Jeffrey , Dalgard Clifton L. ,   The American Genome Center, 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 , López de Munain Adolfo , Pastor Pau , Mir Pablo , Singleton Andrew ,   on behalf of the International Parkinson Disease Genomics Consortium
Published: October 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 PD genome‐wide association study restricted to a single country.MethodsWe 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.ResultsWe 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.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 to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society