The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population‐Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight. Issue 12 (29th October 2019)

• Record Type: Journal Article
• 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.; 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;
• Other Names: Noyce Alastair J investigator.; Kaiyrzhanov Rauan investigator.; Middlehurst Ben investigator.; Kia Demis A investigator.; Tan Manuela investigator.; Houlden Henry investigator.; Morris Huw R investigator.; Plun-Favreau Helene investigator.; Holmans Peter investigator.; Hardy John investigator.; Trabzuni Daniah investigator.; Bras Jose investigator.; PhD John Quinn investigator.; Mok Kin Y investigator.; Kinghorn Kerri J. investigator.; Billingsley Kimberley investigator.; Wood Nicholas W investigator.; Lewis Patrick investigator.; Schreglmann Sebastian investigator.; Guerreiro Rita investigator.; Lovering Ruth investigator.; R'Bibo Lea investigator.; Manzoni Claudia investigator.; Rizig Mie investigator.; Ryten Mina investigator.; Guelfi Sebastian investigator.; Escott-Price Valentina investigator.; Chelban Viorica investigator.; Foltynie Thomas investigator.; Williams Nigel investigator.; Morrison Karen E. investigator.; Brice Alexis investigator.; Danjou Fabrice investigator.; Lesage Suzanne investigator.; Corvol Jean-Christophe investigator.; Martinez Maria investigator.; Schulte Claudia investigator.; Brockmann Kathrin investigator.; Simón-Sánchez Javier investigator.; Heutink Peter investigator.; Rizzu Patrizia investigator.; Sharma Manu investigator.; Gasser Thomas investigator.; Nicolas Aude investigator.; Cookson Mark R investigator.; Bandres-Ciga Sara investigator.; Blauwendraat Cornelis investigator.; Craig David W. investigator.; Faghri Faraz investigator.; Gibbs J Raphael investigator.; Hernandez Dena G. investigator.; Keuren-Jensen Kendall Van investigator.; Shulman Joshua M. investigator.; Iwaki Hirotaka investigator.; Leonard Hampton L. investigator.; Nalls Mike A. investigator.; Robak Laurie investigator.; Lubbe Steven investigator.; Finkbeiner Steven investigator.; Mencacci Niccolo E. investigator.; Lungu Codrin investigator.; Singleton Andrew B investigator.; Scholz Sonja W. investigator.; Reed Xylena investigator.; Alcalay Roy N. investigator.; Gan-Or Ziv investigator.; Rouleau Guy A. investigator.; Krohn Lynne investigator.; van Hilten Jacobus J investigator.; Marinus Johan investigator.; Adarmes-Gómez Astrid D. investigator.; Aguilar Miquel investigator.; Alvarez Ignacio investigator.; Alvarez Victoria investigator.; Barrero Francisco Javier investigator.; Yarza Jesús Alberto Bergareche investigator.; Bernal-Bernal Inmaculada investigator.; Blazquez Marta investigator.; Bonilla-Toribio Marta investigator.; Botía Juan A. investigator.; Boungiorno María Teresa investigator.; Buiza-Rueda Dolores investigator.; Cámara Ana investigator.; Carrillo Fátima investigator.; Carrión-Claro Mario investigator.; Cerdan Debora investigator.; Clarimón Jordi investigator.; Compta Yaroslau investigator.; de la Casa Beatríz investigator.; Diez-Fairen Monica investigator.; Dols-Icardo Oriol investigator.; Duarte Jacinto investigator.; Duran Raquel investigator.; Escamilla-Sevilla Francisco investigator.; Ezquerra Mario investigator.; Feliz Cici investigator.; Fernández Manel investigator.; Fernández-Santiago Rubén investigator.; Garcia Ciara investigator.; García-Ruiz Pedro investigator.; Gómez-Garre Pilar investigator.; Heredia Maria Jose Gomez investigator.; Gonzalez-Aramburu Isabel investigator.; Pagola Ana Gorostidi investigator.; Hoenicka Janet investigator.; Infante Jon investigator.; Jesús Silvia investigator.; Jimenez-Escrig Adriano investigator.; Kulisevsky Jaime investigator.; Labrador-Espinosa Miguel A. investigator.; Lopez-Sendon Jose Luis investigator.; Arregui Adolfo López de Munain investigator.; Macias Daniel investigator.; Torres Irene Martínez investigator.; Marín Juan investigator.; Marti Maria Jose investigator.; Martínez-Castrillo Juan Carlos investigator.; Méndez-del-Barrio Carlota investigator.; González Manuel Menéndez investigator.; Mata Marina investigator.; Mínguez Adolfo investigator.; Mir Pablo investigator.; Rezola Elisabet Mondragon investigator.; Pagonabarraga Javier investigator.; Pascual-Sedano Berta investigator.; Pastor Pau investigator.; Errazquin Francisco Perez investigator.; Periñán-Tocino Teresa investigator.; Ruiz-Martínez Javier investigator.; Ruz Clara investigator.; Rodriguez Antonio Sanchez investigator.; Sierra María investigator.; Suarez-Sanmartin Esther investigator.; Tabernero Cesar investigator.; Tartari Juan Pablo investigator.; Tejera-Parrado Cristina investigator.; Tolosa Eduard investigator.; Valldeoriola Francesc investigator.; Vargas-González Laura investigator.; Vela Lydia investigator.; Vives Francisco investigator.; Zimprich Alexander investigator.; Pihlstrom Lasse investigator.; Toft Mathias investigator.; Koks Sulev investigator.; Taba Pille investigator.; Hassin-Baer Sharon investigator.; Dalgard Clifton L. investigator.; Adeleye Adelani investigator.; Soltis Anthony R. investigator.; Alba Camille investigator.; Viollet Coralie investigator.; Bacikova Dagmar investigator.; Hupalo Daniel N. investigator.; Sukumar Gauthaman investigator.; Pollard Harvey B. investigator.; Wilkerson Matthew D. investigator.; Martinez Elisa McGrath investigator.;
• Is Part Of: Movement disorders. Volume 34:Issue 12(2019)
• Page Start: 1851
• Page End: 1863
• Publication Date: 2019-10-29
• Subjects: age at onset -- Parkinson's disease -- polygenic risk score -- risk haplotype -- Spanish population; Movement disorders -- Periodicals; 610
• DOI: 10.1002/mds.27864
• Languages: English
• ISSNs: 0885-3185

Abstract

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. © 2019 International Parkinson and Movement Disorder Society