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      The Human Genome Project and Its Impact on Psychiatry

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      Annual Review of Neuroscience

      Annual Reviews

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          Abstract

          There has been substantial evidence for more than three decades that the major psychiatric illnesses such as schizophrenia, bipolar disorder, autism, and alcoholism have a strong genetic basis. During the past 15 years considerable effort has been expended in trying to establish the genetic loci associated with susceptibility to these and other mental disorders using principally linkage analysis. Despite this, only a handful of specific genes have been identified, and it is now generally recognized that further advances along these lines will require the analysis of literally hundreds of affected individuals and their families. Fortunately, the emergence in the past three years of a number of new approaches and more effective tools has given new hope to those engaged in the search for the underlying genetic and environmental factors involved in causing these illnesses, which collectively are among the most serious in all societies. Chief among these new tools is the availability of the entire human genome sequence and the prospect that within the next several years the entire complement of human genes will be known and the functions of most of their protein products elucidated. In the meantime the search for susceptibility loci is being facilitated by the availability of single nucleotide polymorphisms (SNPs) and by the beginning of haplotype mapping, which tracks the distribution of clusters of SNPs that segregate as a group. Together with high throughput DNA sequencing, microarrays for whole genome scanning, advances in proteomics, and the development of more sophisticated computer programs for analyzing sequence and association data, these advances hold promise of greatly accelerating the search for the genetic basis of most mental illnesses while, at the same time, providing molecular targets for the development of new and more effective therapies.

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          Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.

          Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11-16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.
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            The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey.

            Major depression is a frequent and disabling psychiatric disorder in the United States. This report examines the prevalence and risk factor profile of both pure and comorbid major depression according to data from the National Comorbidity Survey. To estimate the prevalence of psychiatric comorbidity in the United States, a national sample of 8,098 persons 15-54 years of age from the 48 conterminous states was surveyed with a modified version of the Composite International Diagnostic Interview. From the survey data the prevalence of current (30-day) major depression was estimated to be 4.9%, with a relatively higher prevalence in females, young adults, and persons with less than a college education. The prevalence estimate for lifetime major depression was 17.1%, with a similar demographic distribution. Both 30-day and lifetime prevalence estimates were higher than estimates from the earlier Epidemiologic Catchment Area study. When pure major depression was compared with major depression co-occurring with other psychiatric disorders, the risk factor profiles exhibited clear differences. These findings suggest a greater burden of major depression in community-dwelling persons than has been estimated from previous community samples. The risk factor profile showed significant differences between persons with pure and combined major depression.
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              Autism as a strongly genetic disorder: evidence from a British twin study

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                Author and article information

                Journal
                Annual Review of Neuroscience
                Annu. Rev. Neurosci.
                Annual Reviews
                0147-006X
                1545-4126
                March 2002
                March 2002
                : 25
                : 1
                : 1-50
                Affiliations
                [1 ]National Institute of Mental Health, Bethesda, Maryland 20892;
                Article
                10.1146/annurev.neuro.25.112701.142853
                12052903
                © 2002

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