Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder.

Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with "exemplary phenotypes"-those whose clinical features are reliably associated with LiR and non-response (LiNR)-are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a "clinical exemplar score," which measures the degree to which a subject's clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the "best clinical exemplars") were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the "poor clinical exemplars"). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer's amyloid-secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers.

A 40-bp VNTR polymorphism in the 3'-untranslated region of DAT1/SLC6A3 is associated with ADHD but not with alcoholism.

BACKGROUND: ADHD and alcoholism are psychiatric diseases with pathophysiology related to dopamine system. DAT1 belongs to the SLC6 family of transporters and is involved in the regulation of extracellular dopamine levels. A 40 bp variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region of DAT1/SLC6A3 gene was previously reported to be associated with various phenotypes involving disturbed regulation of dopaminergic neurotransmission. METHODS: A total of 1312 subjects were included and genotyped for 40 bp VNTR polymorphism of DAT1/SLC6A3 gene in this study (441 alcoholics, 400 non-alcoholic controls, 218 ADHD children and 253 non ADHD children). Using miRBase software, we have performed a computer analysis of VNTR part of DAT1 gene for presence of miRNA binding sites. RESULTS: We have found significant relationships between ADHD and the 40 bp VNTR polymorphisms of DAT1/SLC6A3 gene (P < 0.01). The 9/9 genotype appeared to reduce the risk of ADHD about 0.4-fold (p < 0.04). We also noted an occurrence of rare genotypes in ADHD (frequency different from controls at p < 0.01). No association between alcoholism and genotype frequencies of 40 bp VNTR polymorphism of DAT1/SLC6A3 gene has been detected. CONCLUSIONS: We have found an association between 40 bp VNTR polymorphism of DAT1/SLC6A3 gene and ADHD in the Czech population; in a broad agreement with studies in other population samples. Furthermore, we detected rare genotypes 8/10, 7/10 and 10/11 present in ADHD boys only and identified miRNAs that should be looked at as potential novel targets in the research on ADHD.

Association between Val66Met polymorphism of Brain-Derived Neurotrophic Factor (BDNF) gene and a deficiency of colour vision in alcohol-dependent male patients.

Brain-derived neurotrophic factor (BDNF) is a protein encoded, in humans, by BDNF gene on chromosome 11. BDNF protects adult neurons and promotes growth and differentiation during ontogenetic development but the nature and magnitude of its effects could be influenced by functional polymorphisms. The BDNF polymorphism Val66Met (rs6265) has been studied in the context of etiology of mental diseases including alcoholism. Alcoholism - a complex disorder known to be linked to several genes - has multiple manifestations, including sensory deficits such as those affecting vision. In the present study we examined a relationship between the Val66Met polymorphism, alcohol dependence and colour vision deficiency (CVD) in 167 alcohol-dependent men and 289 control male subjects. Statistical analysis revealed that almost half (about 48%) of the alcohol dependent men had a CVD. In addition we found that CVD was significantly associated (P=0.005) with the Val66Met polymorphism. The A allele containing 66Met promotes BDNF expression and this may protect humans against CVD induced by long-term excessive alcohol intake. The present findings indicate that alcohol-induced CVD does not depend solely on excessive alcohol consumption but is significantly influenced by genetic predisposition in the form of a specific BDNF polymorphism.

Heterogeneity of the risk of suicidal behavior in bipolar-spectrum disorders.

OBJECTIVES: The risk of suicidal behavior is substantially elevated in major affective disorders (AD). In bipolar disorder (BD), as many as 15% of patients may commit suicide and family history of suicide is recognized as one of the most important risk factors. Lithium reduces the rates of suicidal behavior in BD, especially in patients who achieve full mood stabilization. Yet even patients who continue experiencing mood episodes do benefit from anti-suicidal properties of lithium. These observations raise questions about the nature of the relationship between the neurobiological mechanisms of BD and suicide, namely whether they are shared or independent. METHODS: We studied the distribution of suicides and suicide attempts in 539 subjects from 78 families of probands with major AD, all responders to lithium prophylaxis. A Cox proportional hazard regression model was used to assess the contribution of several independent variables to the risks of AD, BD, and suicidal behavior. RESULTS: The lifetime prevalence of BD was significantly greater among first-degree relatives of suicide than non-suicide probands (22% versus 11%) and the prevalence of BD in families was associated with an increased risk of developing mood disorder and subsequently committing or attempting suicide (p = 0.003). Families fell into 1 of 3 groups, corresponding to a low (<0.1%), intermediate (17.8%), and high (87.8%) risk for suicide in affectively ill subjects. CONCLUSIONS: Suicidal behavior is distributed unevenly in families of probands with BD, aggregating in a subset of families. Our results also suggest that partially overlapping sets of genetic factors may underlie BD and suicide.

Psychobiology of dissociation and its clinical assessment.

OBJECTIVE: Dissociation is often defined as partial or total disconnection between memories of the past, awareness of identity and of immediate sensations, and control of bodily movements, often resulting from traumatic experiences, intolerable problems, or disturbed relationships. This type of reaction to a psychological and/or physical trauma has often various neurobiological consequences and its clinical assessment has received enormous interest in recent psychological and neuroscience research. METHODS: Psychometric parameters of the Czech version of the Dissociative Experiences Scale were tested from the viewpoints of internal consistency, validity and factor structure, using data from a sample of n=783 adults, divided into three groups (epilepsy n=243, depression n=357, norm n=183), average age 39 years, SD=13.5. RESULTS: Findings of this study demonstrated that reliability, validity and factor structure of the Czech version of the Dissociative Experiences Scale correspond to those of the original English version. CONCLUSIONS: The Czech version of the questionnaire may be considered a suitable tool for estimating subjectively experienced dissociative symptoms.

The association between high-activity COMT allele and alcoholism.

OBJECTIVES: The catechol-O-methyltransferase (COMT) is an enzyme involved in the metabolism of dopamine, adrenaline and noradrenaline. The Val158Met polymorphism of the COMT gene has been previously associated with a variability of the COMT activity, and alcoholism. The aim of the present association study was to examine the relationship between the Val158Met polymorphism of the COMT gene and dispositions to alcoholism. METHODS: In our case control study we analyzed DNA samples from 799 subjects in total (279 male alcoholics and 120 female alcoholics, 151 male controls and 249 female controls). The restriction analysis for the detection of the Val158Met polymorphism was used. RESULTS: We found a relationship between the Val158Met polymorphism of the COMT gene and alcoholism in male subjects. We found the significant difference between male alcoholics and male controls in allele and genotype frequencies (p<0,007; and p<0,04 respectively). CONCLUSIONS: Our study confirmed the relationship between the COMT polymorphism and alcoholism in the Czech male population.

Association between -174 G/C polymorphism of interleukin-6 gene and alcoholism.

OBJECTIVES: IL-6 plays the role as a physiological neuromodulator involved in dopaminergic, serotonergic and other neurotransmissions. The aim of the present association study was to examine the effect of the G/C -174 polymorphism of the IL-6 gene on disposition to alcoholism. METHODS: We investigated the relationship between the G/C -174 polymorphism of the IL-6 gene and alcohol dependence in 281 alcoholics and 242 control subjects. RESULTS: The significant difference in G allele frequency between alcoholic group (0.52) and control group (0.59) was found (P < 0.03). CONCLUSION: To our knowledge, this is the first finding providing evidence for an association between alcoholism and the polymorphism of the IL-6 gene. The background of the relationship between the IL-6 gene and alcoholism is discussed.