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.
Subject(s)
Parkinson Disease/genetics , 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 , Spain , Ubiquitin-Protein Ligases/geneticsABSTRACT
INTRODUCTION: Though a disproportionate rate of atrophy in the medial temporal lobe (MTA) represents a reliable marker of Alzheimer's disease (AD) pathology, measurement of the MTA is not currently widely used in daily clinical practice. This is mainly because the methods available to date are sophisticated and difficult to implement in clinical practice (volumetric methods), are poorly explored (linear and planimetric methods), or lack objectivity (visual rating). Here, we aimed to compare the results of a manual planimetric measure (the yearly rate of absolute atrophy of the medial temporal lobe, 2D-yrA-MTL) with the results of an automated volumetric measure (the yearly rate of atrophy of the hippocampus, 3D-yrA-H). METHODS: A series of 1.5T MRI studies on 290 subjects in the age range of 65-85 years, including patients with AD (n = 100), mild cognitive impairment (MCI) (n = 100), and matched controls (n = 90) from the AddNeuroMed study, were examined by two independent subgroups of researchers: one in charge of volumetric measures and the other in charge of planimetric measures. RESULTS: The means of both methods were significantly different between AD and the other two diagnostic groups. In the differential diagnosis of AD against controls, 3D-yrA-H performed significantly better than 2D-yrA-MTL while differences were not statistically significant in the differential diagnosis of AD against MCI. CONCLUSION: Automated volumetry of the hippocampus is superior to manual planimetry of the MTL in the diagnosis of AD. Nevertheless, the 2D-yrAMTL is a simpler method that could be easily implemented in clinical practice when volumetry is not available.
