The dysbindin gene in major depression: an association study.

The pathophysiological mechanisms, as well as the molecular loci of antidepressant drug action have not yet been established, but recent models proposed that several adaptive mechanisms in signal transduction cascades beyond the receptor and reuptake systems are involved in antidepressant action and play an important role in the etiology of affective disorders. In this context, the dysbindin gene (dystrobrevin-binding-protein 1, DTNBP1), which was recently reported to be associated with schizophrenia seems to be an interesting candidate gene for affective disorders. Dysbindin is widely expressed in the human brain and binds to the dystrophin-associated protein complex (DPC) which appears to be involved in signal transduction pathways, which have been repeatedly investigated and described as altered or disturbed in affective disorders [McLeod et al. [2003: Psychopharmacol Bull 35:24-41]; Brambilla et al. [2003: Mol Psychiatry 8:721-737]]. Therefore, we investigated whether five SNPs in the dysbindin gene could be susceptibility factors in the ethiology of major depression or for the response to antidepressant treatment in a sample of 293 patients compared to 220 healthy controls. Applying single SNP evaluation, as well as haplotype analysis we could not detect an association between the dysbindin polymorphisms and major depression or the response to antidepressant treatment. In conclusion, our results suggest that SNPs in the dysbindin gene are unlikely to play a major role in the pathophysiology of major depression or are in linkage disequilibrium (LD) with a neighboring mutation or gene. Further analysis are needed to confirm these results.

Beta-1-adrenergic receptor gene in major depression: influence on antidepressant treatment response.

Noradrenergic dysfunction has been implicated in the development of affective disorders. beta-adrenergic receptors (betaARs) mediate the response to norephinephrine, are coupled to the cAMP signaling cascade, supposed to be altered in their density and/or sensitivity in depression, and down regulated in several brain regions after long term treatment with different but not all antidepressants. A recently identified functional polymorphism in the beta(1)-adrenergic receptor (G1165C) leading to the amino acid variation Gly389Arg was associated with an enhanced coupling to the stimulatory G(s)-protein and increased adenylyl cyclase activation, disturbances which are often observed in affective disorders. Therefore, we investigated whether this beta(1)AR polymorphism is associated with major depression or with the response to antidepressant treatment in a sample of 259 patients compared to 206 healthy controls. Although we could not detect an association between the beta(1)AR polymorphism and major depression we found a tendency for a relation between CC homozygosity and a better and even faster response to antidepressant treatment in those patients, which were treated with antidepressants affecting directly or indirectly the beta(1)AR system (tricyclic antidepressants, noradrenergic and serotonergic specific agents, selective noradrenaline reuptake inhibitors) determined by the HAMD and CGI score (P = 0.05). However, after correction for multiple testing (Bonferroni) these results did not remain significant. Nevertheless, these findings suggest that the presence of the C allele might be an indicator for antidepressant treatment response.

Analysis of polymorphisms in the alpha-subunit of the olfactory G-protein Golf in lithium-treated bipolar patients.

OBJECTIVE: This study examines the alpha-subunit of the olfactory G-protein (G(olf)) as a possible candidate gene for bipolar disorder. The alpha-subunit of the G(olf) gene maps to a region on chromosome 18p that has been implicated in several linkage studies as a potential site of a bipolar disorder susceptibility loci. METHODS: We investigated whether two polymorphisms in the alpha-subunit of the G(olf) gene (A-->G in intron 3 and T-->G in intron 10) are associated with bipolar disorder in a sample of 149 bipolar patients under lithium treatment compared with 139 healthy controls using haplotype analysis. RESULTS: There was no evidence for an association between the investigated polymorphisms in the G(olf) gene and bipolar disorders, as well as to response to lithium treatment or common side effects, like hand tremor, weight gain and cognitive dysfunction. CONCLUSION: The results of the present study do not support the hypothesis that the G(olf) gene is a major susceptibility factor for bipolar disorders.

Association analysis of a polymorphism in the G-protein stimulatory alpha subunit in patients with major depression.

Growing evidence suggests that G-proteins may be involved in pathogenesis and treatment of affective disorders. Several studies have reported altered levels and/or activities of stimulatory G-proteins in depression. The aim of this study was to investigate whether a polymorphism in the stimulatory alpha subunit of G-proteins (T/C point mutation in exon 5; ATT --> ATC at codon 131) is associated with major depression or response to antidepressant treatment. Therefore, we performed a case-control association study with 212 depressive patients and 137 healthy, unrelated controls. There was no evidence for an association between the investigated polymorphism in the G(alpha)(s) gene and major depression, as well as to treatment response. The results of our study are in concordance with recently published findings which do not support the hypothesis that the gene for the stimulatory alpha subunit of G-proteins is a major susceptibility factor in the pathophysiology of major depression.

Identification of a naturally occurring polymorphism in the promoter region of the norepinephrine transporter and analysis in major depression.

Disturbances in the noradrenergic neurotransmission system have been implicated in the etiology of mood disorders. The norepinephrine transporter (NET) is a main target of antidepressant action and was shown to be dysregulated in major depression. Despite the clinical and physiological significance of NET gene regulation, little is known about the transcriptional control mechanisms governing its expression. Since it is well established that affective disorders have a genetic component with many genes of small effect contributing to the genetic susceptibility of depression, the NET gene is an interesting candidate gene for affective disorders. In a search for polymorphisms or mutations in the 5' flanging region of the NET gene we sequenced approximately 1000 bp upstream of the first codon in the NET gene promoter in 100 patients with major depression and 100 healthy controls. We identified a so far unknown T --> C polymorphism 182 bp upstream of the start codon in a transcriptional relevant region. In a case control association study we investigated the newly identified T-182C polymorphism and an already known G1287A polymorphism in exon 9 of the NET gene in a sample of 193 patients with major depression and 136 healthy, non-related controls. No statistical significant differences between patients and controls were found for any of the analyzed polymorphisms, either in the genotype distribution or in the allele frequencies. Our results suggest that the investigated polymorphisms are not major susceptibility factors in the etiology of major depression.

Analysis of polymorphisms in the olfactory G-protein Golf in major depression.

It is well established that G-proteins represent essential regulatory components in transmembrane signaling. The alpha subunit of the olfactory G-protein Golf (GNAL) maps to a region on chromosome 18 where linkage to affective disorders has been reported, as well as a parent-of-origin effect in affective disorders with some markers near the locus for the alpha subunit of the Golf gene. We investigated whether two polymorphisms in the alpha subunit of the Golf gene (A-->G in intron 3, and T-->G in intron 10) are associated with major depression in 176 major depressive patients compared with 145 healthy control subjects, and additionally tested for a parent-of-origin effect in separated gender groups. In the control group, we found a significant increase in the G-allele frequency of the intron 3 polymorphism in females (P=0.0036, odds ratio=2.13, 95% confidence interval=1.29-3.54, Fisher's Exact Test). In patients, we found a similar tendency for higher G-allele frequencies in females. Concerning the intron 10 polymorphism, no differences in the genotype or allele frequencies were detectable for any of the separated gender groups. Also, the total patient and control groups showed no differences in allele or genotype frequencies for any of the investigated polymorphisms. The results of this study agree with the reported parent-of-origin effects on chromosome 18, but do not support the hypothesis that the Golf gene is a major susceptibility factor for major depression.