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

Research output: Contribution to journalArticlepeer-review

Authors

  • American Genome Center

Colleges, School and Institutes

External organisations

  • Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA)
  • National Institutes of Health
  • 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 Hospitals NHS Foundation Trust
  • 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

© 2019 International Parkinson and Movement Disorder Society.

Details

Original languageEnglish
Pages (from-to)1851-1863
Number of pages13
JournalMovement Disorders
Volume34
Issue number12
Publication statusPublished - Dec 2019