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Mapping the gene network landscape of Alzheimer's disease through integrating genomics and transcriptomics.

ABSTRACT: Integration of multi-omics data with molecular interaction networks enables elucidation of the pathophysiology of Alzheimer's disease (AD). Using the latest genome-wide association studies (GWAS) including proxy cases and the STRING interactome, we identified an AD network of 142 risk genes and 646 network-proximal genes, many of which were linked to synaptic functions annotated by mouse knockout data. The proximal genes were confirmed to be enriched in a replication GWAS of autopsy-documented cases. By integrating the AD gene network with transcriptomic data of AD and healthy temporal cortices, we identified 17 gene clusters of pathways, such as up-regulated complement activation and lipid metabolism, down-regulated cholinergic activity, and dysregulated RNA metabolism and proteostasis. The relationships among these pathways were further organized by a hierarchy of the AD network pinpointing major parent nodes in graph structure including endocytosis and immune reaction. Control analyses were performed using transcriptomics from cerebellum and a brain-specific interactome. Further integration with cell-specific RNA sequencing data demonstrated genes in our clusters of immunoregulation and complement activation were highly expressed in microglia.

SUBMITTER: Rosenthal SB

PROVIDER: S-EPMC8906581 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Mapping the gene network landscape of Alzheimer's disease through integrating genomics and transcriptomics.

Rosenthal Sara Brin SB Wang Hao H Shi Da D Liu Cin C Abagyan Ruben R McEvoy Linda K LK Chen Chi-Hua CH

PLoS computational biology 20220225 2

Integration of multi-omics data with molecular interaction networks enables elucidation of the pathophysiology of Alzheimer's disease (AD). Using the latest genome-wide association studies (GWAS) including proxy cases and the STRING interactome, we identified an AD network of 142 risk genes and 646 network-proximal genes, many of which were linked to synaptic functions annotated by mouse knockout data. The proximal genes were confirmed to be enriched in a replication GWAS of autopsy-documented c ...[more]

PMID: 35213535

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Dataset Information

Mapping the gene network landscape of Alzheimer's disease through integrating genomics and transcriptomics.

Publications

Mapping the gene network landscape of Alzheimer's disease through integrating genomics and transcriptomics.

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