Publication: Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project.
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Date
2019-08-28
Authors
Moreno-Grau, Sonia
de Rojas, Itziar
Hernández, Isabel
Quintela, Inés
Montrreal, Laura
Alegret, Montserrat
Hernández-Olasagarre, Begoña
Madrid, Laura
González-Perez, Antonio
Maroñas, Olalla
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Abstract
Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.
Description
MeSH Terms
Aged
Alzheimer Disease
Dementia
Endophenotypes
Female
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide
Spain
Alzheimer Disease
Dementia
Endophenotypes
Female
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide
Spain
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CIE Terms
Keywords
Alzheimer's disease, Biological pathway, Cerebral amyloid angiopathy, GWAS, Vascular pathology