A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder.

The genetic basis of bipolar disorder has long been thought to be complex, with the potential involvement of multiple genes, but methods to analyze populations with respect to this complexity have only recently become available. We have carried out a genome-wide association study of bipolar disorder by genotyping over 550,000 single-nucleotide polymorphisms (SNPs) in two independent case-control samples of European origin. The initial association screen was performed using pooled DNA, and selected SNPs were confirmed by individual genotyping. While DNA pooling reduces power to detect genetic associations, there is a substantial cost saving and gain in efficiency. A total of 88 SNPs, representing 80 different genes, met the prior criteria for replication in both samples. Effect sizes were modest: no single SNP of large effect was detected. Of 37 SNPs selected for individual genotyping, the strongest association signal was detected at a marker within the first intron of diacylglycerol kinase eta (DGKH; P=1.5 x 10(-8), experiment-wide P<0.01, OR=1.59). This gene encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway. This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk. Bipolar disorder may be a polygenic disease.

Depressive-like behavior and stress reactivity are independent traits in a Wistar Kyoto x Fisher 344 cross.

Depression is a heritable disorder that is often precipitated by stress. Abnormalities of the stress-reactive hypothalamic-pituitary-adrenal (HPA) axis are also common in depressed patients. In animal models, the forced swim test (FST) is the most frequently used test of depressive-like behavior. We have used a proposed animal model of depression, the Wistar Kyoto (WKY) rat, to investigate the relationship as well as the mode of inheritance of FST behaviors and HPA measures. Through reciprocal breeding of WKY and F344 parent strains and brother-sister breeding of the F1 generation, we obtained 486 F2 animals. Parent, F1 and F2 animals were tested in the FST. Blood samples were collected for determination of basal and stress (10-min restraint) plasma corticosterone (CORT) levels, and adrenal weights were measured. We found that all measures were heritable to some extent and that this heritability was highly sex dependent. Both correlation and factor analyses of the F2 generation data demonstrate that FST behavior and HPA axis measures are not directly related. Thus, the underlying genetic components of depressive-like behavior and HPA axis abnormalities are likely to be disparate in the segregating F2 generation of a WKY x F344 cross.

Novel animal models of affective disorders.

Is there an appropriate animal model for human affective disorders? The traditional difficulties in accepting animal models for psychopathology stem from the argument that there is no evidence for concluding that what occurs in the brain of the animal is equivalent to what occurs in the brain of a human. However, if one models any or some core aspects of affective disorder, this model can become an invaluable tool in the analysis of the multitude of causes, genetic, environmental, or pharmacological, that can bring about symptoms homologous to those of patients with affective disorders. Animal models can also allow the study of the mechanisms of specific behaviors, their pathophysiology, and can aid in developing and predicting therapeutic responses to pharmacologic agents. Although animals exhibit complex and varied social and emotional behaviors for which well-validated and standardized measures exist, an understanding that a precise replica of human affective disorders cannot be expected in a single animal model is crucial. Instead, a good animal model of a human disorder should fulfill as many of the four main criteria as possible: (1) strong behavioral similarities, (2) common cause, (3) similar pathophysiology, and (4) common treatment. An animal model fulfilling any or most of these criteria can be used to elucidate the mechanisms of the specific aspect of the model that is homologous to the human disorder. A wide range of animal models of affective disorders, primarily depression, has been developed to date. They include models in which "depressive behavior" is the result of genetic selection or manipulation, environmental stressors during development or in adulthood, or pharmacologic treatments. The assessment of these animal models is based either on behavioral tests measuring traits that are homologous to symptoms of the human disorder they model, or behavioral tests responsive to appropriate pharmacologic treatments. The goal of this review is to focus on relatively recent developments of selected models, to aid in understanding their strengths and weaknesses, and to help those choosing the difficult task of developing novel animal models of affective disorders. The ideal animal model of affective disorders of the future would be an endogenous, genetic model that reiterates the essential, core aspects of the human disease and responds to the standard regimens of therapy. Because complex diseases have been approached from the genetic startpoint by using rodent models, a genetic model of affective disorder would open up possibilities for genetic analysis of polygenic traits that seem to underlie these disorders.

[Diagnostic effectiveness of determining the activity of certain serum enzymes in alcoholism patients]. / Diagnosticheskaia éffektivnost' opredeleniia aktivnosti nekotorykh syvorotochnykh fermentov u bol'nykh alkogolizmom.

Activities of alcohol, aldehyde dehydrogenases (ADH, A1DH, respectively) and gamma-glutamyl transferase (GGT) were estimated in blood serum of patients with Stages I-III alcoholism (54 men) on admission to the hospital, within 1 hr after ethanol testing (in a dose of 0.4 g/kg of body mass) and during the treatment course. Distinct activation of ADH and GGT and decrease in activity of A1DH were found in the patients as compared with healthy volunteers. Alcohol test did not alter noticeably the enzymatic activity studied. The activity of ADH and GGT was normalized in patients with Stages I-II alcoholism during the treatment course. A1DH exhibited the highest diagnostic efficacy, whose sensitivity and specificity were 92% and 84%, respectively; those for ADH 74% and 86% and for GGT 44% and 90%, respectively. Simultaneous estimation of the activity of the three enzymes improved the sensitivity and efficacy of diagnostic technique and enabled the test to be used as an additional criterion in the diagnosis of alcoholism and in the evaluation of the patients' state and therapeutical efficacy.

A new contrast agent for oral cholecystography: iopronic acid (Oravue).

In a preliminary study to determine the safety and minimal effective dose in patients with impaired hepatic function, the cholecystographic agent iopronic acid (Oravue, research contrast material from Squibb) was well tolerated in single oral doses of 1.5, 3.0, 4.5, or 6.0 g. None of the patients experienced clinical adverse reactions. The radiologic results were generally poor, as anticipated for patients with total serum bilirubin concentrations of 2.0-11.4 mg/100 ml. In a subsequent double-blind controlled study in patients without hapatic dysfunction, 4.5 g of iopronic acid or 3.0 g of iopanoic acid (Telepaque, Winthrop) was given to two groups of 90 patients each. Serial radiographs were obtained 13, 14, 15, and 16 hr after ingestion of the drug. Both drugs were highly effective cholecystographic agents, producing visualization in 88% of the patients. Although not statistically significant, a repeat dose was required for visualization in only 4% of the patients given iopronic acid compared to 9% of the patients given iopanoic acid. Visualization was nearly always observed on the first film obtained 13 hr after drug administration. The contrast agents were similar in terms of safety.