Genetic architecture of hippocampus subfields volumes in Alzheimer's disease.

Abstract

The hippocampus is a heterogeneous structure, comprising histologically and functionally distinguishable hippocampal subfields. The volume reductions in hippocampal subfields have been demonstrated to be linked with Alzheimer's disease (AD). The aim of our study is to investigate the hippocampal subfields' genetic architecture based on the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set. After preprocessing the downloaded genetic variants and imaging data from the ADNI database, a co-sparse reduced rank regression model was applied to analyze the genetic architecture of hippocampal subfields volumes. Homology modeling, docking, molecular dynamics simulations, and Co-IP experiments for protein-protein interactions were used to verify the function of target protein on hippocampal subfields successively. After that, the association analysis between the candidated genes on the hippocampal subfields volume and clinical scales were performed. The results of the association analysis revealed five unique genetic variants (e.g., ubiquitin-specific protease 10 [USP10]) changed in nine hippocampal subfields (e.g., the granule cell and molecular layer of the dentate gyrus [GC-ML-DG]). Among five genetic variants, USP10 had the strongest interaction effect with BACE1, which affected hippocampal subfields verified by MD and Co-IP experiments. The results of association analysis between the candidated genes on the hippocampal subfields volume and clinical scales showed that candidated genes influenced the volume and function of hippocampal subfields. Current evidence suggests that hippocampal subfields have partly distinct genetic architecture and may improve the sensitivity of the detection of AD.