The genetic architecture of Parkinson disease in Spain: characterizing population-specific risk, differential haplotype structures, and providing etiologic insight

摘要: 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 neurodegenerative diseases. Objectives To perform largest Parkinson disease (PD) genome-wide association study (GWAS) restricted to a single country. Methods We performed GWAS both risk PD age-at-onset (AAO) in 7,849 Spanish individuals. Further analyses included population-specific haplotype assessments, polygenic scoring through machine learning, Mendelian randomization expression methylation data gain insight into disease-associated loci, heritability estimates, correlations burden analyses. Results identified novel signal at PARK2 associated with AAO. replicated four independent signals risk, including SNCA, LRRK2, KANSL1/MAPT HLA-DQB1. A significant trend smaller haplotypes known loci was found compared similar studies non-Spanish origin. Seventeen PD-related genes showed functional consequence via two-sample datasets. Long runs homozygosity 28 genes/loci were be enriched cases versus controls. Conclusions Our demonstrate utility substructure future fine-mapping efforts, showing how leveraging unique diverse histories can benefit complex present points major hallmark etiology Spain.