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• W22344070 abstract "The disease signature of major depressive disorder is distributed across multiple physical scales and investigative specialties, including genes, cells and brain regions. No single mechanism or pathway currently implicated in depression can reproduce its diverse clinical presentation, which compounds the difficulty in finding consistently disrupted molecular functions. We confront these key roadblocks to depression research - multi-scale and multi-factor pathology - by conducting parallel investigations at the levels of genes, neurons and brain regions, using transcriptome networks to identify collective patterns of dysfunction. Our findings highlight how the collusion of multi-system deficits can form a broad-based, yet variable pathology behind the depressed phenotype. For instance, in a variant of the classic lethality-centrality relationship, we show that in neuropsychiatric disorders including major depression, differentially expressed genes are pushed out to the periphery of networks. At the level of cellular function, we develop a molecular signature of depression based on cross-species analysis of human and mouse microarrays from depression-affected areas, and show that these genes form a tight module related to oligodendrocyte function and neuronal growth/structure. At the level of brain-region communication, we find a set of genes and hormones associated with the loss of feedback between the amygdala and anterior cingulate cortex, based on a novel assay of interregional expression synchronization termed gene coordination. These results indicate that in the absence of a single pathology, depression may be created by dysynergistic effects among genes, cell-types and brain regions, in what we term the floodgate model of depression. Beyond our specific biological findings, these studies indicate that interaction networks are a coherent framework in which to understand the faint expression changes found in depression and complex neuropsychiatric disorders." @default.
• W22344070 created "2016-06-24" @default.
• W22344070 creator A5000435625 @default.
• W22344070 date "2011-03-18" @default.
• W22344070 modified "2023-09-27" @default.
• W22344070 title "Finding the pathology of major depression through effects on gene interaction networks" @default.
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