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Finding the pathology of major depression through effects on gene interaction networks

Gaiteri, Christopher (2011) Finding the pathology of major depression through effects on gene interaction networks. Doctoral Dissertation, University of Pittsburgh.

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    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 gene 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 gene interaction networks are a coherent framework in which to understand the faint expression changes found in depression and complex neuropsychiatric disorders.


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    Item Type: University of Pittsburgh ETD
    ETD Committee:
    ETD Committee TypeCommittee MemberEmailORCID
    Committee ChairSommer, Marcmarc.sommer@duke.edu
    Committee MemberSibille, Etiennesibilleel@upmc.edu
    Committee MemberTseng, Georgectseng@pitt.edu
    Committee MemberRubin, Jonathanjonrubin@pitt.edu
    Committee MemberRinaman, LindaRinaman@bns.pitt.edu
    Committee MemberOldham, Michaeloldhamm@stemcell.ucsf.edu
    Title: Finding the pathology of major depression through effects on gene interaction networks
    Status: Unpublished
    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 gene 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 gene interaction networks are a coherent framework in which to understand the faint expression changes found in depression and complex neuropsychiatric disorders.
    Date: 18 March 2011
    Date Type: Completion
    Defense Date: 22 February 2011
    Approval Date: 18 March 2011
    Submission Date: 07 March 2011
    Access Restriction: No restriction; The work is available for access worldwide immediately.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    URN: etd-03072011-230448
    Uncontrolled Keywords: depression; major depression; microarray; network analysis; small-world; graph theory; scale-free
    Schools and Programs: School of Medicine > Neurobiology
    Date Deposited: 10 Nov 2011 14:32
    Last Modified: 24 Feb 2012 13:30
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-03072011-230448/, etd-03072011-230448

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