Search

Alzheimer's disease (AD) has a strong genetic predisposition. However, its risk genes remain incompletely identified. We developed an Alzheimer's brain gene network-based approach to predict AD-associated genes by leveraging the functional pattern of known AD-associated genes. Our constructed network outperformed existing networks in predicting AD genes. We then systematically validated the predictions using independent genetic, transcriptomic, proteomic data, neuropathological and clinical data. First, top-ranked genes were enriched in AD-associated pathways. Second, using external gene expression data from the Mount Sinai Brain Bank study, we found that the top-ranked genes were significantly associated with neuropathological and clinical traits, including the Consortium to Establish a Registry for Alzheimer's Disease score, Braak stage score and clinical dementia rating. The analysis of Alzheimer's brain single-cell RNA-seq data revealed cell-type-specific association of predicted genes with early pathology of AD. Third, by interrogating proteomic data in the Religious Orders Study and Memory and Aging Project and Baltimore Longitudinal Study of Aging studies, we observed a significant association of protein expression level with cognitive function and AD clinical severity. The network, method and predictions could become a valuable resource to advance the identification of risk genes for AD., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Motivation Alzheimer's disease (AD) is a complex brain disorder with risk genes incompletely identified. The candidate genes are dominantly obtained by computational approaches. In order to obtain biological insights of candidate genes or screen genes for experimental testing, it is essential to assess their relevance to AD. A platform that integrates different types of omics data and approaches would facilitate the analysis of candidate genes and is in great need. Results We report AlzCode, a platform for multiview analysis of genes related to AD. First, this platform integrates a rich collection of functional genomic data, including expression data of AD samples (gene expression, single-cell RNA-seq data and protein expression), AD-specific biological networks (co-expression networks and functional gene networks), neuropathological and clinical traits (CERAD score, Braak staging score, Clinical Dementia Rating, cognitive function and clinical severity) and general data such as protein–protein interaction, regulatory networks, sequence similarity and miRNA-target interactions. These data provide basis for analyzing genes from different views. Second, the platform integrates multiple approaches designed for the various types of data. We implement functions to analyze both individual genes and gene sets. We also compare AlzCode with two existing platforms for AD analysis, which are Agora and AD Atlas. We pinpoint the features of each platform and highlight their differences. This platform would be valuable to the understanding of AD genetics and pathological mechanisms. Availability and implementation AlzCode is freely available at: http://www.alzcode.xyz. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]