Neuroscience
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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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Attention influences many aspects of cognitive development. Variations in the catechol-O-methyltransferase (COMT) gene, known to affect dopamine neurotransmission, have frequently been found to influence attention in adults and older children. In this paper we examined 2 year old children and found that variation in the COMT gene influenced attention in a task involving looking to a sequence of visual stimuli. ⋯ The Val(108/158)Met polymorphism of COMT is commonly used to determine allelic groups, but recently haplotypes of several polymorphisms within this gene have been shown to be more strongly associated with perceived pain. Since attention and pain both involve the activation of the anterior cingulate gyrus in imaging studies, we compared the Val(108/158)Met influence with the COMT haplotypes and found the latter to be more predictive of attention. Our results confirm that important aspects of cognitive development including attention depend on the interaction of genes and early environment.
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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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Late-onset Alzheimer's disease is a common complex disorder of old age. Though these types of disorders can be highly heritable, they differ from single-gene (Mendelian) diseases in that their causes are often multifactorial with both genetic and environmental components. Genetic risk factors that have been firmly implicated in the cause are mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes, which are found in large multi-generational families with an autosomal dominant pattern of disease inheritance, the apolipoprotein E (APOE)epsilon4 allele and the sortilin-related receptor (SORL1) gene. ⋯ The "endophenotype" approach is an alternative method for measuring phenotypic variation that may facilitate the identification of susceptibility genes for complexly inherited traits. The usefulness of endophenotypes in genetic analyses of normal brain morphology and, in particular for Alzheimer's disease will be reviewed as will the implications of these findings for models of disease causation. Given that the pathways from genotypes to end-stage phenotypes are circuitous at best, identifying endophenotypes more proximal to the effects of genetic variation may expedite the attempts to link genetic variants to disorders.