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

被引：44

作者：

Bandres-Ciga, Sara ^{[1
,2
]}

Ahmed, Sarah ^{[1
,3
]}

Sabir, Marya S. ^{[1
,3
]}

Blauwendraat, Cornelis ^{[1
]}

Adarmes-Gomez, Astrid D. ^{[4
,5
]}

Bernal-Bernal, Inmaculada ^{[4
,5
]}

Bonilla-Toribio, Marta ^{[4
,5
]}

Buiza-Rueda, Dolores ^{[4
,5
]}

Carrillo, Fatima ^{[4
,5
]}

Carrion-Claro, Mario ^{[4
,5
]}

Gomez-Garre, Pilar ^{[4
,5
]}

Jesus, Silvia ^{[4
,5
]}

Labrador-Espinosa, Miguel A. ^{[4
,5
]}

Macias, Daniel ^{[4
,5
]}

Mendez-del-Barrio, Carlota ^{[4
,5
]}

Perinan-Tocino, Teresa ^{[4
,5
]}

Tejera-Parrado, Cristina ^{[4
,5
]}

Vargas-Gonzalez, Laura ^{[4
,5
]}

Diez-Fairen, Monica ^{[6
,7
]}

Alvarez, Ignacio ^{[6
,7
]}

Pablo Tartari, Juan ^{[6
,7
]}

Buongiorno, Mariateresa ^{[6
,7
]}

Aguilar, Miquel ^{[6
,7
]}

Gorostidi, Ana ^{[5
,8
,9
]}

Alberto Bergareche, Jesus ^{[5
,8
,10
]}

Mondragon, Elisabet ^{[5
,8
,10
]}

Vinagre-Aragon, Ana ^{[10
]}

Croitoru, Ioana ^{[8
]}

Ruiz-Martinez, Javier ^{[5
,8
,10
]}

Dols-Icardo, Oriol ^{[5
,11
,12
]}

Kulisevsky, Jaime ^{[5
,13
]}

Marin-Lahoz, Juan ^{[5
,13
]}

Pagonabarraga, Javier ^{[5
,13
]}

Pascual-Sedano, Berta ^{[5
,13
]}

Ezquerra, Mario ^{[5
,14
,15
,16
]}

Camara, Ana ^{[5
,14
,15
,16
]}

Compta, Yaroslau ^{[5
,14
,15
,16
]}

Fernandez, Manel ^{[5
,14
,15
,16
]}

Fernandez-Santiago, Ruben ^{[5
,14
,15
,16
]}

Munoz, Esteban ^{[5
,14
,15
,16
]}

Tolosa, Eduard ^{[5
,14
,15
,16
]}

Valldeoriola, Francesc ^{[5
,14
,15
,16
]}

Gonzalez-Aramburu, Isabel ^{[5
,17
,18
]}

Sanchez Rodriguez, Antonio ^{[5
,17
,18
]}

Sierra, Maria ^{[5
,17
,18
]}

Menendez-Gonzalez, Manuel ^{[19
,20
]}

Blazquez, Marta ^{[19
,20
]}

Garcia, Ciara ^{[19
,20
]}

Martin, Esther Suarez-San ^{[19
,20
]}

Garcia-Ruiz, Pedro ^{[21
]}

机构：

[1] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[2] Inst Invest Biosanitaria Granada Ibs GRANADA, Granada, Spain

[3] NINCDS, Neurodegenerat Dis Res Unit, NIH, Bethesda, MD 20892 USA

[4] Univ Seville, Hosp Univ Virgen del Rocio, Serv Neurol & Neurofisiol Clin,CSIC, Unidad Trastornos Movimiento,Inst Biomed Sevilla, Seville, Spain

[5] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain

[6] Univ Hosp Mutua Terrassa, Fundacio Docencia & Recerca Mutua Terrassa, Barcelona, Spain

[7] Univ Hosp Mutua Terrassa, Movement Disorders Unit, Dept Neurol, Barcelona, Spain

[8] Biodonostia Hlth Res Inst, Neurodegenerat Disorders Area, San Sebastian, Spain

[9] Inst Invest Biodonostia, Plataforma Genom, San Sebastian, Spain

[10] Hosp Univ Donostia, Unidad Trastornos Movimiento, Dept Neurol, San Sebastian, Spain

[11] IIB St Pau, Genet Neurodegenerat Disorders Unit, Barcelona, Catalonia, Spain

[12] Univ Autonoma Barcelona, Barcelona, Catalonia, Spain

[13] Univ Autonoma Barcelona, Movement Disorders Unit, Dept Neurol, St Pau Hosp, Barcelona, Catalonia, Spain

[14] IDIBAPS Inst Invest Biomed, Lab Parkinson Dis & Other Neurodegenerat Movement, Barcelona, Catalonia, Spain

[15] Univ Barcelona, Maria de Maetzu Ctr, Unitat Parkinson & Trastorns Moviment, Serv Neurol,Hosp Clin Barcelona, Catalonia, Spain

[16] Univ Barcelona, Maria de Maetzu Ctr, Inst Neurociencies, Catalonia, Spain

[17] Hosp Univ Marques Valdecilla IDIVAL, Serv Neurol, Santander, Spain

[18] Univ Cantabria, Santander, Spain

[19] Hosp Univ Cent Asturias, Serv Neurol, Asturias, Spain

[20] Inst Invest Sanitaria Principado Asturias ISPA, Asturias, Spain

[21] Inst Invest Sanitaria Fdn Jimenez Diaz, Dept Neurol, Madrid, Spain

[22] Hosp Univ Ramon y Cajal, Dept Neurol, Inst Ramon y Cajal Invest Sanitaria, Madrid, Spain

[23] Hosp Univ Fdn Alcorcon, Serv Neurol, Madrid, Spain

[24] Univ Granada, Ctr Invest Biomed, Fac Med, Granada, Spain

[25] Univ Granada, Dept Fisiol, Fac Med, Granada, Spain

[26] Univ Granada, Hosp Univ San Cecilio, Serv Neurol, Granada, Spain

[27] Hosp Univ Virgen de las Nieves, Serv Neurol, Granada, Spain

[28] Hosp Gen Segovia, Serv Neurol, Segovia, Spain

[29] Hosp Univ Virgen de la Victoria, Serv Neurol, Malaga, Spain

[30] Hosp Univ Infanta Sofia, Dept Neurol, Madrid, Spain

[31] Hosp Univ & Politecn La Fe, Dept Neurol, Inst Invest Sanitaria La Fe, Valencia, Spain

[32] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA

[33] Uniformed Serv Univ Hlth Sci, Amer Genome Ctr, Collaborat Hlth Initiat Res Program, Bethesda, MD 20814 USA

[34] NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[35] NIA, Computat Biol Grp, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[36] Univ Murcia, Dept Ingn Informac & Comunicac, Murcia, Spain

[37] UCL, Inst Neurol, Dept Mol Neurosci, London, England

[38] Univ Southampton, Dept Neurol, Fac Med, Southampton, Hants, England

[39] Univ Birmingham, Birmingham, W Midlands, England

[40] Sandwell & West Birmingham Hosp NHS Trust, Birmingham, W Midlands, England

[41] UCL, Dept Clin Neurosci, London, England

[42] Univ Tubingen, Dept Neurodegenerat Dis, Hertie Inst Clin Brain Res, Tubingen, Germany

[43] German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany

[44] Data Tecn Int, Glen Echo, MD USA

[45] Johns Hopkins Med Ctr, Dept Neurol, Baltimore, MD USA

[46] Inst Recerca St Joan Deu, Lab Neurogenet & Med Mol, Barcelona, Spain

[47] Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain

[48] Hosp Univ Cent Asturias, Genet Lab, Asturias, Spain

[49] Univ Basque Country, Hosp Univ Donostia, Serv Neurol, Dept Neurociencias, San Sebastian, Spain

来源：

MOVEMENT DISORDERS | 2019年 / 34卷 / 12期

基金：

美国国家卫生研究院;

关键词：

age at onset; Parkinson's disease; polygenic risk score; risk haplotype; Spanish population; GLUCOCEREBROSIDASE MUTATIONS; ASSOCIATION; EFFICIENT; GWAS; TOOL;

D O I：

10.1002/mds.27864

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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. (c) 2019 International Parkinson and Movement Disorder Society

引用

页码：1851 / 1863

页数：13

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