Intermediate phenotypes and genetic mechanisms of psychiatric disorders.

Unit for Systems Neuroscience in Psychiatry, Clinical Brain Disorders Branch, National Institute for Mental Health, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
Nature reviews. Neuroscience (Impact Factor: 31.38). 11/2006; 7(10):818-27. DOI: 10.1038/nrn1993
Source: PubMed

ABSTRACT Genes are major contributors to many psychiatric diseases, but their mechanisms of action have long seemed elusive. The intermediate phenotype concept represents a strategy for characterizing the neural systems affected by risk gene variants to elucidate quantitative, mechanistic aspects of brain function implicated in psychiatric disease. Using imaging genetics as an example, we illustrate recent advances, challenges and implications of linking genes to structural and functional variation in brain systems related to cognition and emotion.

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    ABSTRACT: Serotonin transporter gene variants are known to interact with stressful life experiences to increase chances of developing affective symptoms, and these same variants have been shown to influence amygdala reactivity to affective stimuli in non-psychiatric populations. The impact of these gene variants on affective neurocircuitry in anxiety and mood disorders has been studied less extensively. Utilizing a triallelic assay (5-HTTLPR and rs25531) to assess genetic variation linked with altered serotonin signaling, this fMRI study investigated genetic influences on amygdala and anterior insula activity in 50 generalized anxiety disorder patients, 26 of whom also met DSM-IV criteria for social anxiety disorder and/or major depressive disorder, and 39 healthy comparison subjects. A Group x Genotype interaction was observed for both the amygdala and anterior insula in a paradigm designed to elicit responses in these brain areas during the anticipation of and response to aversive pictures. Patients who are S/LG carriers showed less activity than their LA/LA counterparts in both regions and less activity than S/LG healthy comparison subjects in the amygdala. Moreover, patients with greater insula responses reported higher levels of intolerance of uncertainty, an association that was particularly pronounced for patients with two LA alleles. A genotype effect was not established in healthy controls. These findings link the serotonin transporter gene to affective circuitry findings in anxiety and depression psychopathology and further suggest that its impact on patients may be different from effects typically observed in healthy populations.
    PLoS ONE 02/2015; 10(2):e0115820. DOI:10.1371/journal.pone.0115820 · 3.53 Impact Factor
  • 01/2014; 1(1):6. DOI:10.1186/2051-6673-1-6
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    ABSTRACT: Background: Quantitative genetic analysis of basic mouse behaviors is a powerful tool to identify novel genetic phenotypes contributing to neurobehavioral disorders. Here, we analyzed genetic contributions to single-trial long-term social and non-social recognition and subsequently studied the functional impact of an identified candidate gene on behavioral development. Methods: Genetic mapping of single-trial social recognition was performed in chromosome substitution strains (CSS), a powerful tool for detecting quantitative trait loci (QTL) of complex traits. Follow-up occurred by generating and testing knockout mice of a selected QTL candidate gene. Functional characterization of these mice was performed through behavioral and neurological assessments across developmental stages and analyses of gene expression and brain morphology. Results: CSS14 mapping studies revealed an overlapping QTL related to long-term social and object recognition harboring Pcdh9, a cell-adhesion gene previously associated with autism spectrum disorder. Specific long-term social and object recognition deficits were confirmed in homozygous (KO) Pcdh9-deficient mice, while heterozygous mice only showed long-term social recognition impairment. The recognition deficits in KO mice were not associated with alterations in perception, multi-trial discrimination learning, sociability, behavioral flexibility or fear memory. Rather, KO mice showed additional impairments in sensorimotor development reflected by early touch-evoked biting, rotarod performance, and sensory gating deficits. This profile emerged with structural changes in deep layers of sensory cortices, where Pcdh9 is selectively expressed. Conclusions: This behavior-to-gene study implicates Pcdh9 in cognitive functions required for long-term social and non-social recognition. This role is supported by the involvement of Pcdh9 in sensory cortex development and sensorimotor phenotypes.
    Biological psychiatry 02/2015; DOI:10.1016/j.biopsych.2015.01.017 · 9.47 Impact Factor

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