Petr Zvolský

Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium

Genetic mapping studies in bipolar disorder (BD) have been hampered by the unclear boundaries of the phenotypic spectrum, and possibly, by the complexity of the underlying genetic mechanisms, and heterogeneity. Among the suggested approaches to circumvent these problems, a pharmacogenetic strategy has been increasingly proposed. Several studies have indicated that patients with BD who respond well to lithium prophylaxis constitute a biologically distinct subgroup. In this study we have conducted a complete genome scan using 378 markers spaced at an average distance of 10 cM in 31 families ascertained through excellent lithium responders. Response to lithium was evaluated prospectively with an average follow-up of 12 years. Evidence for linkage was found with a locus on chromosome 15q14 (ACTC, lod score = 3.46, locus-specific P-value = 0.000014) and suggestive results were observed for another marker on chromosome 7q11.2 (D7S1816, lod score = 2.68, locus-specific P-value = 0.00011). Other interesting findings were obtained with markers on chromosomes 6 and 22, namely D6S1050 (lod score = 2.0, locus-specific P-value = 0.00004) and D22S420 (lod score = 1.91). Nonparametric linkage analysis provided additional support for the role of these loci. Further analyses of these results suggested that the locus on chromosome 15q14 may be implicated in the etiology of BD, whereas the 7q11.2 locus may be relevant for lithium response. In conclusion, our results provide original evidence suggesting that loci on 15q14 and 7q11.2 may be implicated in the pathogenesis of BD responsive to lithium.

Human circadian rhythm in serum melatonin in short winter days and in simulated artificial long days

Serum melatonin rhythm was studied in 6 human subjects experiencing short winter days resembling light/dark (LD) 8:16 h and in 6 subjects exposed at the same time to a long, LD 16:8 h skeleton photoperiod, with 3 h of bright light in the evening and again in the morning; 4 out of the 6 subjects entrained to the simulated summer photoperiod within 3 days. In the synchronized subjects, the nocturnal melatonin signal was 3 h shorter than in those experiencing just winter days. The data indicate that humans are able to respond to environmental day length by forming a proper endogenous photoperiodic signal.

Association and Linkage Studies of CRH and PENK Genes in Bipolar Disorder: A Collaborative IGSLI Study

Corticotropin-releasing hormone (CRH) and proenkephalin (PENK) are hypothalamic peptides involved in the stress response and hypothalamic-pituitary axis regulation. Previous research has implicated these peptides in the pathogenesis of affective disorders. In this study we investigated two polymorphisms located in the genes that code for CRH and PENK by means of association and linkage analyses. A total of 138 bipolar patients and 108 controls were included in the association study. In addition, 24 families were available for linkage analysis, including six families of probands with documented periodic positivity of dexamethasone suppression tests (DST) during remission. We found no association of bipolar disorder with either gene. Similarly, we did not find any evidence of linkage (P = 0.56 for CRH and 0.52 for PENK) in the entire sample or in the subsample of families of DST positive probands. In conclusion, our study does not support the hypothesis that genes coding for CRH or PENK contribute to the genetic susceptibility to bipolar disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:178-181, 2000.

Polyglutamine tracts: no evidence of a major role in bipolar disorder.

SIR — Over the last 3 years, a large number of studies have focused on a possible role of trinucleotide repeats, particularly expanded CAG/CTG repeats, in bipolar disorder (BD). The investigation of trinucleotide repeats has been supported by reports of genetic anticipation as well as studies using the repeat expansion detection (RED) technique. Recently, two independent studies have reported the presence of polyglutamine tracts in proteins of about 50–60 kDa extracted from lymphoblastoid cell lines of schizophrenic patients. In some of these cases, the polyglutamine tract appeared to co-segregate within the family with the illness. This finding is of interest, as CAG codons are translated into glutamine. In this study we tested for the presence of expanded polyglutamine tracts in a well-characterized cohort of bipolar patients. We investigated lymphoblastoid cell lines from 70 bipolar patients and 73 normal controls using Western blot analysis with 1C2—a monoclonal antibody that detects proteins containing polyglutamine tracts. Patients with BD were recruited from centers that collaborate in the International Group for the Study of Lithium (IGSLI). We have focused on lithium-responsive BD, aiming to reduce genetic heterogeneity. This strategy is supported by a number of genetic-epidemiological and neuroendocrinological studies which are discussed in detail in Grof et al. Control subjects for this study were 73 psychiatrically normal individuals. Of these, 34 were screened with a SADS-L interview and RDC criteria. The remaining controls were subjects without any record of psychiatric disorders whose samples were available for this study. All patients and controls were Caucasians of Western and Central European descent and were matched, whenever possible, for geographical origin. Figure 1 shows a Western blot of patients, normal controls as well as a positive control (SCA3 patient). In all cases, the 1C2 antibody detected a band of strong intensity of around 49 kDa that corresponds to the

Maintenance of a circadian phase adjustment of the human melatonin rhythm following artificial long days

In winter, a 5-day exposure of 4 human subjects to a skeleton photoperiod, with 3 h of bright light in the evening and again in the morning, phase advanced the morning serum melatonin offset by 1-3 h as compared with the original winter melatonin rhythm pattern. The phase advance persisted for 3 days even after the bright light withdrawal. The data indicate that the long skeleton photoperiod had a prevailing phase-advancing effect on the melatonin rhythm and its underlying pacemaker. The maintenance of the phase advance might be due to the fixed sleep-wake schedule.

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.

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.