Journal
MOVEMENT DISORDERS
Volume 34, Issue 12, Pages 1851-1863Publisher
WILEY
DOI: 10.1002/mds.27864
Keywords
age at onset; Parkinson's disease; polygenic risk score; risk haplotype; Spanish population
Categories
Funding
- Intramural Research Program of the National Institutes of Health (National Institute on Aging, National Institute of Neurological Disorders and Stroke) [1ZIA-NS003154-03, Z01-AG000949-02, Z01-ES101986]
- Department of Defense [W81XWH-09-2-0128]
- Michael J Fox Foundation for Parkinson's Research
- ISCIII [PI 15/0878, PI 15/01013]
- Spanish Ministry of Economy and Competitiveness [PI14/01823, PI16/01575, PI18/01898, SAF2006-10126, SAF2010-22329-C02-01, SAF2013-47939-R]
- Fondo Europeo de Desarrollo Regional (FEDER)
- Consejeria de Economia, Innovacion, Ciencia y Empleo de la Junta de Andalucia [CVI-02526, CTS-7685]
- Consejeria de Salud y Bienestar Social de la Junta de Andalucia [PI-0437-2012, PI-0471-2013]
- Sociedad Andaluza de Neurologia
- Jacques and Gloria Gossweiler Foundation
- Fundacion Alicia Koplowitz
- Fundacion Mutua Madrilena
- Miguel Servet (ISCIII16 FEDER) programme
- Nicolas Monardes (Andalusian Ministry of Health) programme
- Juan Rodes programme (ISCIII-FEDER)
- Rio Hortega programme (ISCIII-FEDER)
- VPPI-US from the Universidad de Sevilla
- Junta de Andalucia [PSI2014-57643]
- Andalusian Society of Neurology
- MRC [G0701075, MR/K01417X/1, G0901254, MR/N026004/1, UKDRI-1009] Funding Source: UKRI
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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
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