Neuroscience
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Bipolar disorder is a mood disorder characterized by impairing episodes of mania and depression. Twin studies have established that bipolar disorder is among the most heritable of medical disorders and efforts to identify specific susceptibility genes have intensified over the past two decades. The search for genes influencing bipolar disorder has been complicated by a paucity of animal models, limited understanding of pathogenesis, and the genetic and phenotypic complexity of the syndrome. ⋯ Nevertheless, genomewide association analysis, which has successfully identified susceptibility genes for a variety of complex disorders, has begun to implicate specific genes for bipolar disorder (DGKH, CACNA1C, ANK3). The polygenicity of the disorder means that very large samples will be needed to detect the modest effect loci that likely contribute to bipolar disorder. Detailed genetic dissection of the disorder may provide novel targets (both pharmacologic and psychosocial) for intervention.
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Primary torsion dystonia (PTD) is a chronic movement disorder manifested clinically by focal or generalized sustained muscle contractions, postures, and/or involuntary movements. The most common inherited form of PTD is associated with the DYT1 mutation on chromosome 9q34. A less frequent form is linked to the DYT6 locus on chromosome 8q21-22. ⋯ The DTI data raise the possibility that metabolic abnormalities in mutation carriers reflect adaptive responses to developmental abnormalities in the intrinsic connectivity of the motor pathways. Moreover, findings of increased motor activation responses in these subjects are compatible with the reductions in cortical inhibition that have been observed in this disorder. Future research will focus on clarifying the relationship of these changes to clinical penetrance in dystonia mutation carriers, and the reversibility of disease-related functional abnormalities by treatment.
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Various genes are known to modulate the delicate balance of dopamine in prefrontal cortex and influence cortical information processing. Catechol-O-methyltransferase (COMT) on chromosome 22q11 is the most widely studied of these genes. ⋯ We review how Val158Met has been used to help develop and validate behavioral and neurophysiological phenotypes, as a critical tool in dissecting overlapping neural functional systems and exploring interactions within and between genes, and in exploring how gene effects on cognition are modulated by environmental, demographic and developmental factors. Despite the impressive range of findings, the COMT story is also a bracing reminder of how much work remains to translate this knowledge into practical clinical applications.
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Imaging techniques are a potentially powerful method of identifying phenotypes that are associated with, or are indicative of, a vulnerability to developing major depressive disorder (MDD). Here we identify seven promising MDD-associated traits identified by magnetic resonance imaging (MRI) or positron emission tomography (PET). We evaluate whether these traits are state-independent, heritable endophenotypes, or state-dependent phenotypes that may be useful markers of treatment efficacy. ⋯ Potentially indicative of inter-study variation in MDD etiology or mood state, both increased and decreased binding potential of the 5-HT transporter has been reported. Challenges facing the field include the problem of phenotypic and etiological heterogeneity, technological limitations, the confounding effects of medication, and non-disease related inter-individual variation in brain morphology and function. Further advances are likely as epigenetic, copy-number variant, gene-gene interaction, and genome-wide association (GWA) approaches are brought to bear on imaging data.
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There has been a dramatic rise in gene x environment studies of human behavior over the past decade that have moved the field beyond simple nature versus nurture debates. These studies offer promise in accounting for more variability in behavioral and biological phenotypes than studies that focus on genetic or experiential factors alone. They also provide clues into mechanisms of modifying genetic risk or resilience in neurodevelopmental disorders. ⋯ In this paper, we describe research that focuses on the impact of a polymorphism in a brain-derived neurotrophic factor (BDNF) gene, known to be involved in learning and development. Specifically we present findings that assess the effects of genotypic and environmental loadings on neuroanatomic and behavioral phenotypes across development. The findings illustrate the use of a genetic mouse model that mimics the human polymorphism, to constrain the interpretation of gene-environment interactions across development in humans.