Positional cloning and comprehensive mutation analysis of a Japanese family with lithium-responsive bipolar disorder identifies a novel DOCK5 mutation.

Bipolar disorder (BD) is a severe psychiatric disorder characterized by the recurrence of depressive and manic episodes. Its heritability is high, and many linkage and association studies have been performed. Although various linkage regions and candidate genes have been reported, few have shown sufficient reproducibility, and none have identified the pathogenic genes based on the results of the linkage analysis. To find functional variants that are expected to be rare and have strong genetic effects, we recruited ten healthy individuals, two individuals with unknown status, and six patients with BD or recurrent major depressive disorder (MDD) from a Japanese family consisting of 21 members. We performed a genome-wide linkage analysis using a 100K single-nucleotide polymorphism (SNP) array and microsatellite markers to narrow linkage regions within this family. Subsequently, we performed whole-exome sequencing for two patients with BD to identify genetic mutations in the narrowed linkage regions. Then, we performed co-segregation analysis for DNA variants obtained from the results of the exome sequencing. Finally, we identified a rare heterozygous mutation in exon 31 of DOCK5 (c.3170A>G, p.E1057G). Convergent functional genomics analysis revealed that DOCK5 was listed as one of the biomarkers for mood state and suicidality. Although DOCK5 is still a functionally unknown gene, our findings highlight the possibility of a pathological relationship between BD and DOCK5.

Preclinical voluntary drinking models for alcohol abstinence-induced affective disturbances in mice.

Negative reinforcement is widely thought to play an important role in chronic alcohol-use disorders (AUDs), and high comorbidity between AUDs and affective disorders highlights the importance of investigating this relationship. Prominent models posit that repeated cycles of alcohol (ethanol, EtOH) exposure and withdrawal produce circuit adaptations in the central nervous system that drive a transition from positive- to negative reinforcement-based alcohol seeking. Evidence supporting this theory has accumulated in large part using forced EtOH administration models, such as chronic intragastric gavage and chronic vapor inhalation. However, recent studies utilizing simple voluntary EtOH delivery systems show that forced abstinence from EtOH intake administered by the animal itself can produce evolving and significant affective disturbances, particularly in female C57BL/6J mice. Here, we highlight these recent studies to support the idea that voluntary EtOH administration in mouse models, as well as a protracted abstinence period and less commonly used behavioral tasks, could unveil affective disturbances during abstinence that have remained elusive using high dosage forced EtOH administration paradigms.

[Analysis of insertion-deletion polymorphism in serotonin transporter gene in men of different ethnic appurtenance with acute alcoholic psychosis]. / Analiz insertsionno-deletsionnogo polimorfizma v gene perenoschika serotonina u muzhchin s ostrym alkogol'nym psikhozom raznoi étnicheskoi prinadlezhnosti.

Analysis of insertion-deletion polymorphism of serotonin vector gene (SLC6A4) was carried out in Russian and Tatar men with acute alcoholic psychosis. Significant interpopulation differences in the distribution of SLC6A4 genotype and allele frequencies were revealed. A relationship of L/S gene with the disease was detected in Russians and Tatars, but the presence of heterozygotic genotype was associated with early onset of chronic alcoholization and development of acute alcoholic psychosis in Tatars and with later alcoholization and disease development in Russians. The share of S/S genotype was significantly decreased in Russian patients aged over 35 years, which suggests selection aimed at elimination of short allele homozygotes among patients with this disease and probably different genetic prerequisites for early and late development of the disease in Russians. In Tatars aged over 35 years acute alcoholic psychosis is associated with L/L genotype (RR-3).

[The evaluation of VNTR-polymorphism in the gene of dopamine transporter in men of different nationalities with acute alcoholic psychosis]. / Otsenka VNTR-polimorfizma v gene perenoschika dofamina u muzhchin raznoi etnicheskoi prinadlezhnosti s ostrym alkogol'nym psikhozom.

VNTR-polymorphism of the gene of dopamine transporter (DAT) in men of the Russian and Tatar nationalities with acute alcoholic psychoses was analyzed by method of the polymerase chain reaction. There were no differences in the distribution of frequencies of genotypes and alleles of DAT gene between the populations examined. There was association between an allele variant with 9 units of DAT gene repetition (in homozygous state first of all), and early development of alcoholic dependence and acute alcoholic psychosis.

Genetic predisposition to organ-specific endpoints of alcoholism.

Medical records of the 15,924 twin-pairs in the National Academy of Sciences-National Research Council (NAS-NRC) twin registry were collected for an additional 16 years through 1994 when the surviving twins were aged 67 to 77 years. Compared with earlier analyses (Hrubec, Z, and Omenn, G. S., Alcohol. Clin. Exp. Res., 5:207-215, 1981), when subjects were aged 51 to 61, there were 23% more diagnoses of alcoholism (34.4 per 1,000 prevalence), 32% more diagnoses of alcoholic psychosis (5.4 per 1,000), and 25% more twins with liver cirrhosis (17.7 per 1,000). Overall, 5.3% of the cohort had at least one of the diagnoses related to alcoholism. Probandwise concordance rates (%) were: alcoholism-26.7 monozygotic (MZ), 12.2 dizygotic (DZ) (p < 0.0001); alcoholic psychosis-17.3 MZ, 4.8 DZ (p < 0.05); and cirrhosis-16.9 MZ, 5.3 DZ (p < 0.001). Concordance for any diagnosis related to alcoholism was 30.2 MZ, 13.9 DZ (p < 0.0001). Maximum-likelihood modeling indicated that approximately 50% of the overall variance was due to additive genetic effects; in all diagnosis categories, a totally environmental model gave a significantly poorer fit to the data. Bivariate and trivariate genetic analyses indicated most of the genetic liability for the organ-specific endpoints of psychosis and cirrhosis was due to the shared genetic liability for alcoholism. Once the shared variance with alcoholism was considered, there was no further shared genetic liability for psychosis and cirrhosis. Our results confirm Hrubec and Omenn's conclusion that there was significantly greater concordance in MZ twins-pairs for alcoholic psychosis and cirrhosis in the NAS-NRC twins, and concordance rates remained similar to those reported 16 years earlier. In contrast, we found most of the genetic liability to organ-specific complications of alcoholism was shared with the genetic liability for alcoholism per se; only a small portion of the genetic variance of the individual complications was independent of the genetic predisposition for alcoholism.

[Quantitative EEG, basic disorders and smoking in etiopathogenetically different groups of paranoid-hallucinatory psychoses--an exploratory study]. / Quantitatives EEG, Basisstörungen und Rauchen bei ätiopathogenetisch differenten Gruppen paranoid-halluzinatorischer Psychosen--eine explorative Studie.

We performed an exploratory study of quantitative EEG in aetiopathogenetically different paranoid-hallucinatory psychoses divided into the following groups: a) patients with familial psychoses (n = 12), b) patients with neuropsychological deficits (n = 16), c) patients with alcohol and drug abuse (n = 22) and d) patients with so-called sporadic psychoses (n = 12). We found a significant reduction of relative alpha power in the group with neuropsychological deficits. In the group with familial psychosis there was a significant reduction of absolute delta power and a significant increase of relative beta power and dominant beta frequency, especially for the frontal leads. Patients with drug abuse showed a reduction of absolute beta power and an increase of absolute and relative theta power. The group with sporadic psychosis showed a significant slowing of the dominant beta frequency and a significant increase of the absolute power of fast alpha rhythms. The group with sporadic psychoses showed lowered scores for the paranoid-hallucinatory basic symptom factor. The group with neuropsychological deficits showed the most visceral-somatoform basic symptoms, the highest nicotine consumption, increased dyskinesias and more perinatal complications. This group also showed the highest level of neuroleptic and antiparkinson medication. All in all, the group with neuropsychological deficits showed a complex interaction of somatic-exogenic and medical-iatrogenic factors. Furthermore, there was a significant positive correlation between paranoid-hallucinatory basic symptoms and nicotine abuse and high frequency beta waves.

Psychopathological characteristics in alcohol hallucinosis and paranoid schizophrenia.

In a retrospective study psychopathology, psychiatric family history and demographic data were studied in 53 patients with alcohol hallucinosis and an age- and sex-matched control group of 53 patients with paranoid schizophrenia who had been treated at the Psychiatric Hospital of the University of Munich between 1979 and 1986. The psychopathology was assessed by the AMDP system. The paranoid-hallucinatory symptoms in both conditions were very similar; verbal hallucinations and delusions of reference were most common in both groups. Disorders of ego were found in 87% of the schizophrenics, but only 30% of the alcoholic patients (P less than 0.001). Schizophrenics developed psychosis at a younger age than alcoholics and seemed to have poorer outcome. Patients with alcohol hallucinosis had more relatives with an alcohol history (P less than 0.001), and schizophrenics more relatives with schizophrenic psychosis (P less than 0.001).

Platelet monoamine oxidase, plasma dopamine beta-hydroxylase activity, dementia and family history of alcoholism in chronic alcoholics.

The authors measured platelet monoamine oxidase (MAO) activity and plasma dopamine beta-hydroxylase activity in 36 male chronic alcoholics during a period of non-abstinence, and in 29 normal controls. The influence of family history, dementia, chronicity of drinking and liver injury on the enzyme activities was also examined by multiple regression analysis. Platelet MAO was significantly lower in the alcoholic group. Both enzyme activities were negatively related to the presence of dementia, while low MAO activity was associated with positive family history (parents, sibs) of alcoholism.

Genetic differences in anticonvulsant sensitivity in mouse lines selectively bred for ethanol withdrawal severity.

WSP (withdrawal seizure-prone) mice exhibit approximately 10-fold more severe withdrawal convulsions than WSR (withdrawal seizure-resistant) mice after identical chronic ethanol exposure. Although WSP and WSR mice do not differ in threshold for seizures elicited by electroconvulsive shock (ECS), WSR mice are more sensitive to ethanol-induced elevation of ECS seizure thresholds. The current experiments demonstrated that WSR mice showed more ECS-induced seizure threshold elevation than WSP mice when tested after the administration of C1-C5 straight-chain alcohols. Whereas the brain concentrations of the C1 and C2 alcohols did not differ between the lines, WSP mice tended to have higher brain concentrations than WSR mice of the C3-C5 alcohols, even though they exhibited the smaller behavioral response in all cases. Thus, the difference between WSP and WSR mice was one of neurosensitivity and could not be attributed to pharmacokinetic differences. The WSR line was also more sensitive to ethchlorvynol, methyprylon, barbital, phenobarbital, pentobarbital, diazepam, valproic acid and phenytoin in this test. Examining loss of righting reflex (RR), we found that WSP and WSR mice did not differ in ED50, latency to lose RR or duration of loss of RR. Thus, the genetic anticonvulsant sensitivity difference is not simply a genetic difference in sensitivity to central nervous system depression between the lines. In summary, WSR mice were more sensitive to the anticonvulsant effects of a variety of compounds than WSP mice, suggesting that some genes influence both ethanol withdrawal seizures and ethanol's anticonvulsant effects.

Ethanol withdrawal in mice bred to be genetically prone or resistant to ethanol withdrawal seizures.

We are engaged in a selective breeding program developing lines of mice which differ in severity of withdrawal convulsions after ethanol treatment. Withdrawal seizure prone (WSP) mice show greater handling-induced convulsion scores than withdrawal seizure resistant (WSR) mice after 3 days of ethanol intoxication. In the present experiments, we sought to characterize these mice further as a model of genetic susceptibility to ethanol dependence and withdrawal. During withdrawal after chronic treatment with ethanol, WSP mice displayed more severe handling-induced convulsions and tremor than WSR mice, and tended to show greater reduction of exploratory activity. WSP and WSR mice did not differ in ethanol metabolism after acute treatment with ethanol alone or after chronic treatment with ethanol and pyrazole, an alcohol dehydrogenase inhibitor. Six to 10 hr after an acute injection of ethanol, WSP and WSR mice showed elevated handling-induced convulsions. This elevation was more pronounced in WSP mice than in WSR mice. WSP mice also showed slightly more severe convulsions than WSR mice when treated with saline or pyrazole alone. In summary, WSP and WSR mice treated with identical doses of ethanol differ in several symptoms of withdrawal, whereas not differing in ethanol metabolism. These mice constitute a useful population in which to study the molecular mechanisms of ethanol dependence and withdrawal.

Separate heritability of alcoholism and psychotic symptoms.

The authors identified 259 alcoholic probands and 507 first-degree relatives. Alcoholic relatives of probands with psychotic symptoms were significantly more likely to have psychotic symptoms than those related to probands without psychotic symptoms. This finding suggests separate genetic transmission.

Arylsulfatase A variants in patients with alcoholism.

Leukocytes from 200 mentally ill patients and 100 normal controls were analyzed for electrophoretic variants of arylsulfatase A. Four different variant forms were found in 15 subjects. There is a relatively high occurrence of the arylsulfatase A variants in patients with alcoholism. Twenty-one per cent (12/56) of patients with alcoholism have a variant enzyme. Only one of the 100 normal controls has a variant enzyme. (This single subject was considered normal by the criteria of the study, namely, a self-report of no current medical problem or psychiatric history. However, upon further testing, it was found that this subject has neurological and neuropsychological deficits). The hypothesis is presented that chronic alcohol intake and abnormal arylsulfatase A act in concert to elevate sulfatide levels which results in abnormalities of brain function. If this hypothesis is correct, persons in whom abnormal arylsulfatase A is expressed may be at risk to the neuropathological effects of alcohol.

Genetic correlations with ethanol withdrawal severity.

A major goal of pharmacogenetic research on alcoholism remains the identification of some "marker" that could predict the liability of a particular individual for a genetic susceptibility to develop alcoholism. The present paper presents evidence that the severity of withdrawal from physical dependence on ethanol varies widely among inbred strains of mice, and that withdrawal severity is negatively genetically correlated with initial sensitivity and magnitude of tolerance to ethanol hypothermia. These correlations are supported by differences in hypothermic response between replicate lines of mice genetically selected for susceptibility and resistance to ethanol withdrawal seizures. The genetic relationships reported suggest that the effects of ethanol on thermoregulation in mice may offer a predictive marker for susceptibility to ethanol physical dependence.

Selective breeding in mice for severity of the ethanol withdrawal syndrome.

Starting with a foundation population of 200 genetically heterogeneous mice (HS/Ibg), selective breeding has been initiated for a multivariate index of the ethanol withdrawal syndrome. This paper discusses the advantages of using multivariate indices to define pharmacological concepts. The seven variables included in our multivariate index are described. Because five of the seven variables showed a significant sex difference, separate principal component analyses were performed to establish selection indices appropriate for each sex. The study employs within-family mating to minimize inbreeding and includes replicate high, low, and control lines. These selectively bred lines should eventually provide a useful animal model for studying physiological and neurological mechanisms that may be involved in the ethanol withdrawal syndrome.

Evidence of genetic predisposition to alcoholic cirrhosis and psychosis: twin concordances for alcoholism and its biological end points by zygosity among male veterans.

Medical histories of the 15,924 male twin pairs in the National Academy of Sciences-National Research Council Twin Registry were examined to determine, within pairs, concordances for alcoholism and its medical end points. Prevalences per 1,000 among individual twin subjects were 29.6 for alcoholism, 4.1 for alcoholic psychosis, 14.2 for liver cirrhosis, and 2.1 for pancreatitis. Prevalences were similar to monozygotic (MZ) and dizygotic (DZ) twins. Prevalences in percent among co-twins of diagnosed subjects, that is case-wise twin concordance rates, were, respectively, by diagnosis: alcoholism: 26.3 (MZ), 11.9 (DZ); alcoholic psychosis: 21.1 (MZ), 6.0 (DZ); and liver cirrhosis: 14.6 (MZ), 5.4 (DZ). No twin pairs concordant for pancreatitis were found. The greater concordance for alcoholic psychosis and for liver cirrhosis among MZ than DZ twins could not be explained by the difference in alcoholism concordance between them. The difference in concordance between MZ and DZ twins persisted when, in addition, it was assumed that only half of the actually occurring cases of alcoholism and of each of the end points have been ascertained. These results provide evidence in favor of genetic predisposition to organ-specific complications of alcoholism and should serve to stimulate searches for the underlying biochemical mechanisms.

[Genotypic specificity of schizophrenic psychoses]. / K voprosu o genotipicheskoi spetsifichnosti shizofrenicheskikh psikhozov.

A total of 610 probands with a disease manifestation in childhood, middle and old age and their families were examined by the clinico-genealogical method. The results allowed conclusions that (1) there is an undoubted genetic relationship between schizophrenia of childhood, middle and old age; and that (2) among the closest relatives in families of the probands there is no significant (in comparison to the general population) accumulation of non-schizophrenic pathology. The latter indicates a high genotypic specificity of schizophrenia.