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

TLDR

Large variability among Alzheimer's disease cases hampers genetic discovery and complicates pathway dissection, prompting the GR@ACE genome‑wide study of dementia and its clinical endophenotypes defined by clinical certainty and vascular burden. The study aimed to assess how known AD loci influence clinical endophenotypes, classify them into three categories reflecting disease heterogeneity, and evaluate this effect through meta‑analysis of GR@ACE and additional GWAS datasets. Researchers performed a genome‑wide association study of dementia, assessed known AD loci across endophenotypes, incorporated gene coexpression data for pathway analysis per category, and meta‑an.

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.