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

Mov Disord. 2019 Dec;34(12):1851-1863. doi: 10.1002/mds.27864. Epub 2019 Oct 29.


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.

Keywords: Parkinson's disease; Spanish population; age at onset; polygenic risk score; risk haplotype.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Case-Control Studies
  • Chromosome Mapping
  • Cost of Illness
  • DNA Methylation
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study
  • Genotype
  • Haplotypes
  • Humans
  • Machine Learning
  • Male
  • Middle Aged
  • Multifactorial Inheritance
  • Parkinson Disease / genetics*
  • Spain
  • Ubiquitin-Protein Ligases / genetics


  • Ubiquitin-Protein Ligases
  • parkin protein