RESUMO
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.
Assuntos
Doença de Parkinson/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Mapeamento Cromossômico , Efeitos Psicossociais da Doença , Metilação de DNA , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Espanha , Ubiquitina-Proteína Ligases/genéticaRESUMO
El presente texto, recoge las discusiones y reflexiones derivadas de variasinvestigaciones en las que se describe, analiza y evidencia la participación de los actores que conforman la actual sociedad de la información como constantes de la educación superior en México, los paliativos que de ella se emanan, la transmisión de información y los procesos de formación actuales, el desafío de construir signos y símbolos cuando las señales ya no son controladas por el dispositivo pedagógico tradicional lo que exige, en un contexto cambiante, que la educación superior no sea más un interior autosuficiente, posibilitando la producción de subjetividades por las clases disciplinares y de control, legitimadas por medio de viejas y nuevas tecnologías.
The present text, includes discussions and reflections derived from several studies in which the participation of the actors that make up the current information society as constants of higher education in Mexico are described, analyzed, and madeevident, as well as the palliatives emanating from it, transmission of information and the current training processes, the challenge of building signs and symbols when the signals are no longer controlled by the traditional pedagogical device, which requires, in a changing context, that higher education is no longer a selfsufficient interior, making the production of subjectivity possible by the disciplinary and control classes, legitimized by means of old and new technologies.