Mapping the gene network landscape of Alzheimer's disease through integrating genomics and transcriptomics
| Autor: | Sara Brin Rosenthal, Hao Wang, Da Shi, Cin Liu, Ruben Abagyan, Linda K. McEvoy, Chi-Hua Chen |
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| Přispěvatelé: | Cheng, Feixiong |
| Rok vydání: | 2021 |
| Předmět: |
Aging
Bioinformatics 1.1 Normal biological development and functioning Neurodegenerative Alzheimer's Disease Mathematical Sciences Cellular and Molecular Neuroscience Mice Underpinning research Alzheimer Disease Information and Computing Sciences Acquired Cognitive Impairment Genetics 2.1 Biological and endogenous factors Animals Gene Regulatory Networks Aetiology Molecular Biology Ecology Evolution Behavior and Systematics Ecology Human Genome Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Genomics Biological Sciences Brain Disorders Computational Theory and Mathematics Modeling and Simulation Neurological Dementia Transcriptome Biotechnology Genome-Wide Association Study |
| Zdroj: | PLoS computational biology, vol 18, iss 2 |
| ISSN: | 1553-7358 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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