Results of genome-wide association analysis of dementia and its clinical endophenotypes. The GR@ACE Project.

The Andalusian Institute for Neuroscience (IANEC) has participated in the study of genome of dementia research carried out by the Fundación ACE (GR@ACE) and whose results have just been published in the journal Alzheimer´s and Dementia. This is a genome-wide study of dementia and its clinical endophenotypes, defined on the basis of the clinical certainty of Alzheimer’s disease (AD) and vascular load. The impact of known AD loci through endophenotypes was evaluated to generate categories of loci. Gene co-expression data were incorporated and pathway analysis by category was performed. Finally, to assess the effect of heterogeneity on genetic studies, a GR@ACE series meta-analysis was performed with additional datasets from genome-wide association studies.

The results obtained allowed to classify the 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.

Thus, 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.

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