The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight
Research output: Contribution to journal › Article › peer-review
Authors
Colleges, School and Institutes
External organisations
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA)
- National Eye Institute, National Institutes of Health, Bethesda, Maryland
- National Institute on Aging
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)
- University Hospital Mútua de Terrassa
- Plataforma de Genomica
- Unidad de Trastornos de Movimiento
- Biodonostia Health Research Institute
- Genetics of Neurodegenerative Disorders Unit
- University College London
- Unitat de Parkinson i Trastorns del Moviment. Servicio de Neurologia
- Servicio de Neurología
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)
- Sandwell and West Birmingham Hospitals NHS Trust
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.
Bibliographic note
Details
Original language | English |
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Pages (from-to) | 1851-1863 |
Number of pages | 13 |
Journal | Movement Disorders |
Volume | 34 |
Issue number | 12 |
Publication status | Published - Dec 2019 |