Association of the GABRD gene and childhood-onset mood disorders.

The chromosome 1p36 region was previously indicated as a locus for susceptibility to recurrent major depressive disorder based on a linkage study in a sample of 497 sib pairs. We investigated the gamma-aminobutyric acid A (GABA(A)) delta receptor subunit gene, GABRD, as a susceptibility gene to childhood-onset mood disorders (COMD) because of substantial evidence implicating GABAergic dysfunction in mood disorders and the position of this gene near the 1p36 linkage region. Using a sample consisting of 645 Hungarian families with a child/adolescent proband diagnosed with a mood disorder with the onset of the first episode before age 15, we found some evidence for the association of two polymorphisms located within the gene, rs2376805 and rs2376803, as well as significant evidence for biased transmission of the haplotypes of these two markers (global chi(2) test for haplotypes = 12.746, 3 df, P = 0.0052). Furthermore, significant evidence of association was only observed in male subjects (n = 438) when the results were analyzed by sex (chi(2) = 9.000 1 df, P = 0.003 for rs2376805). This was in contrast with the previous linkage findings, as LOD scores exceeding 3 were only in female-female pairs in that study. These findings point to the GABRD gene as a susceptibility gene for COMD; however, this gene may not explain the previous linkage finding.

Mutation screen and association analysis of the glucocorticoid receptor gene (NR3C1) in childhood-onset mood disorders (COMD).

Depressive disorders are highly heterogeneous psychiatric disorders involving deficits to cognitive, psychomotor, and emotional processing. Considerable evidence links disruption to the hypothalamic-pituitary-adrenal (HPA) axis to the etiology of depression, with specific deficits reported in glucocorticoid receptor (GR)-mediated negative feedback. Given the role of GR-mediated negative feedback in mediating response to stress, and the clear link between stress and depression, it is plausible that polymorphisms in the GR gene (NR3C1) act to increase susceptibility. Maternal behavior in rats epigenetically alters a NGF1-A transcription factor binding-site in the promoter region of the GR gene, providing a mechanism by which environmental cues can regulate GR expression and thus response to stress. The analogous region of the human GR gene (NR3C1) has not been studied, but it is possible that polymorphisms in this region may alter the binding of transcription factors known to regulate GR expression. In this study, we have performed bioinformatic analyses on the promoter region of NR3C1 to identify conserved promoter sequences and predicted transcription factor binding sites. These regions were screened with denaturing high-performance liquid chromatography (DHPLC) and direct re-sequencing, and several novel polymorphic variants were identified. We genotyped nine polymorphisms across NR3C1 in a large sample of Hungarian nuclear families ascertained through affected probands with a diagnosis of childhood-onset mood disorders (COMD). Single-marker analysis provided little evidence for an association of this gene with COMD, but multi-marker analysis across a region of high linkage disequilibrium revealed modest evidence for the biased transmission of several haplotypes.

Cytokine Genes TNF, IL1A, IL1B, IL6, IL1RN and IL10, and childhood-onset mood disorders.

BACKGROUND/AIMS: Inflammatory cytokines induce a behavioral syndrome, known as sickness behavior, that strongly resembles symptoms typically seen in depression. This resemblance has led to the theory that an imbalance of inflammatory cytokine activity may be a contributing factor in depressive disorders. Support for this is found in multiple lines of evidence, such as the effects of cytokines on the activities of the hypothalamic-pituitary-adrenal axis, serotonin and brain-derived neurotrophic factor, and hippocampal function, all of which are implicated in the etiology of depression. In addition, associations between inflammatory activity and depressive symptomology have been documented in a number of studies, and the depressogenic effects of cytokine therapy are well known. Accordingly, given that depression has a substantial genetic basis, genes involved in the regulation of inflammatory cytokine activity are strong candidates for involvement in genetic susceptibility to depressive disorders. Here, we have tested 6 key genes of this type, TNF, IL1A, IL1B, IL6, IL1RN and IL10, as candidates for involvement in childhood-onset mood disorders. METHODS: In this study of 384 families, each ascertained through a child with depression diagnosed before the age of 15 years, 11 polymorphisms of known or likely functional significance (coding and regulatory variants) were analyzed. RESULTS: Testing for biased transmission of alleles from parents to their affected offspring, we found no evidence for an association between childhood-onset mood disorders and any of the polymorphisms, either individually or as haplotypes. CONCLUSION: The present study does not support the involvement of the TNF, IL1A, IL1B, IL6, IL1RN and IL10 variants as major genetic risk factors contributing to early-onset mood disorders.

Association study of the adrenergic receptors and childhood-onset mood disorders in Hungarian families.

The adrenergic system has been implicated in the etiology of depression based on a number of lines of evidence, particularly, the mechanism of some classes of antidepressants which increase the synaptic levels of norepinephrine. Further, several genome scans for mood disorders, both unipolar and bipolar, have indicated linkage to the chromosomal regions of 5q23-q33.3, 8p12-p11.2, 4p16, and 10q24-q26, the location of the adrenergic receptors alpha1B (ADRA1B), beta3 (ADRB3), alpha2C (ADRA2C), alpha2A (ADRA2A), and beta1 (ADRB1). In this manuscript, we report on the relationship of the adrenergic receptors and depression using a family based association approach and 189 families (223 affected children) with childhood-onset mood disorder (COMD) collected in Hungary. We found no significant evidence for an association with any of the 24 markers, in total, tested across these genes using single marker analysis or haplotypes of markers across these genes. The results in the present sample indicate that these nine genes are unlikely to be major susceptibility genes contributing to COMD.

Family- and school-related stresses in depressed Hungarian children.

The aim of the study was 1) to identify recent and past life stresses as having a significant differential risk of childhood depression versus other childhood psychiatric illnesses, and 2) to establish if life stresses shared with other family members had a greater impact on the depression of the child than events of only personal relevance. Using a recently developed semi-structured interview (Diagnostic Evaluation Schedule for Children and Adolescents - Hungarian version, DESCA-H ), 68 life events of a total sample of 526 children were investigated. Two hundred and fifteen depressed preadolescents (mean age 12.73 years, SD 2.58) were compared with identical variables of 311 nondepressed mixed clinical controls (mean age: 10.91 years, SD 2.46) referred to child psychiatry care with other psychiatric symptomatology than depression. The life event questionnaire part of the DESCA-H was administered separately by means of lists of recent (within 1 year) and past stresses (events prior to 1 year before the assessment). With the two series of life stresses, two separate logistic regression analyses were performed. Of past stressors, physical punishment of the child by teachers, serious financial problems of the family and mental health problems of family members were found to be significant predictors of depression. From the series of recent stresses, moving to a new school, somatic illness, death of relatives and mental health disorders of family members were proved to be independent risk factors of depression for the children. The findings suggest that significant stresses of the child shared with other family members dominate in demarcating depressed children from nondepressed ones. School-related stresses are critically discussed.

Are microarousals preceded by electroencephalographic slow wave synchronization precursors of confusional awakenings?

The number of microarousals preceded by electroencephalographic (EEG) slow wave synchronization (MAS) and the number not preceded by EEG slow wave synchronization (K-complexes and/or delta groups) (MA) were analyzed during the first night of sleep in nine young patients with somnambulism and/or sleep terrors and in eight age- and sex-matched controls. While MAs peaked in REM ad intermediate sleep, MASs appeared as a phenomenon of NREM sleep, peaking in stage 2. The number of MASs was significantly greater in all stages of NREM sleep in the patient group, but number and distribution of MAs did not differ between the two groups. In the patient group, the MASs occurred in slow wave sleep (stages 3-4 of each sleep cycle); in controls, MASs occurred infrequently. MASs were frequently associated with automatic chewing movements. The higher frequency of microarousals in the patient group did not result in an increase in time awake during the night. The increase in number of microarousals supports Broughton's hypothesis of the presence of some "arousal disorder" in somnambulism and/or sleep terrors. MASs may be predictive markers of ensuing confusional awakenings.