A variant in the 5-hydroxytryptamine (serotonin) receptor 5A (HTR5A) gene may be involved in the pathogenesis of bipolar disorder, says an international team of scientists, although they urge caution in interpreting the findings.

Despite a wealth of research into the etiology of bipolar disorder and evidence to suggest that it is the result of an interaction between genetic and environmental factors, no single gene has been identified as being definitively associated with the disorder.

Yusuke Nakamura, from the University of Tokyo in Japan, and colleagues genotyped 94 bipolar disorder patients and 184 healthy controls from Bulgaria for 191 single nucleotide polymorphisms (SNPs) in 65 candidate genes using TaqMan and/or Invader assays.

In all, 17 SNPs were significantly associated with bipolar disorder and these were further genotyped in an additional set of 78 bipolar disorder patients and 372 controls, with the results pooled with the previous analysis to give a combined set of 172 patients and 556 controls.

The most significant association with bipolar disorder was found for the rs1800883 SNP in a promoter region of the HTR5A gene, which was unaffected by sequential Bonferroni correction, the team notes in the Journal of Affective Disorders.

Analysis revealed that 56.7% of the patients were homozygous for the G risk allele, compared with 42.1% of controls, giving an odds ratio of 1.80. In addition, the risk allele was more common in patients than in controls, at 73.7% versus 62.1%.

A weak association was also found for the rs6265 SNP located in exon 2 of the brain-derived neurotrophic factor gene, with the risk C allele more frequently seen in patients than controls, while a possible association was observed for the rs5443 SNP in exon 10 of the guanine nucleotide binding protein, beta polypeptide 3 gene. However, neither survived Bonferroni correction.

“In conclusion, our findings suggest that HTR5A gene could be one of many genes of importance in the etiology of bipolar disorder in the Bulgarian population, but the effect by the genetic substitution seemed to be small even if the association is further confirmed,” the team writes.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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Disrupted in schizophrenia 1 (DISC1) gene variants play a role in the development of psychiatric illness yet there is significant heterogeneity in clinically relevant variants between populations, say international scientists.

Although schizophrenia, schizoaffective disorder, bipolar disorder (BD), major depression, autism, and Asperger syndrome have all been linked to DISC1, no actual causal variants have been identified.

William Hennah, from the University of Edinburgh, and colleagues therefore studied 1275 individuals with schizophrenia, nearly 2000 with BD, and more than 2000 healthy controls from four European centers. All participants were genotyped for the presence of 75 single nucleotide polymorphisms (SNPs) in the translin-associated protein X and DISC1 genes, of which 67 were suitable for analysis.

For the combined sample, no SNP survived permutation correction or was significantly associated with schizophrenia or BD. However, the rs1538979 SNP was significantly associated with BD I males in the Finnish group and the rs821577 SNP was significantly linked with BD females in the London group, at odds ratios of 2.73 and 1.64, respectively.

Although unable to survive corrected analysis, the rs821577 SNP G allele was associated with BD in the combined group and BD females, at odds ratios of 1.28 and 1.44, respectively.

Additionally, the rs1538979 SNP T allele was a risk factor for BD in females in the London group and was protective against in schizophrenia in men in the Aberdeen group at odds ratios of 1.50 and 0.55, respectively.

Further analysis revealed that the rs821633 SNP together with the T allele of the rs1538979 SNP were associated with an increased risk for schizophrenia in females. Interestingly, the rs1538979 SNP was a risk factor only in the presence of the rs821633 SNP, while the rs821633 SNP was protective on its own.

The team concludes in the journal Molecular Psychiatry: “Our data provide further genetic support for a role of DISC1 in psychiatric illness, with the same variants on the same gene modulating risk to both BD and schizophrenia, further substantiating the hypothesis that these two separate disorders have overlapping genetic risks.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2009

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None of several polymorphisms of a gene in chromosome 12 previously linked to bipolar disorders are involved in susceptibility to mood disorders, the results of a UK study indicate.

Chromosomal region 12q24 has been implicated in both bipolar disorder and unipolar mood disorder in linkage studies, and the gene P2RX7, which is located within this chromosomal region, has been suggested as a susceptibility gene for bipolar disorder and unipolar depression.

To investigate further, Elaine Green, from the University of Wales College of Medicine in Cardiff, and colleagues studied 687 bipolar I disorder patients, 1036 unipolar recurrent major depression patients, and 1204 healthy controls.

All participants were genotyped for single nucleotide polymorphisms (SNPs) of the P2RX7 gene, including the non-synonymous (missense) SNP rs2230912. This results in amino-acid polymorphism Q460R, which has previously been suggested to be pathologically relevant in mood disorders.

Writing in the American Journal of Medical Genetics Part B Neuropsychiatric Genetics, the team reports that none of the polymorphisms studied had significant allelic or genotypic association with bipolar disorder compared with controls, with unipolar depression compared with controls, or with combined mood disorder compared with controls.

Furthermore, sequencing of two families with chromosome 12-linked bipolar disorder and Darier’s disease did not reveal any rare variants that could explain the previously observed linkage.

The team concludes: “We have found no evidence that the non-synonymous SNP rs2230912 influences susceptibility to mood disorder in our study population…

“Nonetheless it remains possible that variation within parts of the gene that were not well tagged within the current study may influence risk for mood disorder or that the effect in the population we studied was too small to be detected in our sample.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2009

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Patients with broadly defined bipolar schizoaffective features either have a strong genetic contribution to their condition or are genetically homogenous compared with other bipolar groups, conclude UK researchers.

While the descriptive criteria currently used to define psychiatric phenotypes have acceptable reliability, the phenotypes themselves are not necessarily valid clinical entities, which may have an impact on the basis for clinical practice.

To examine the relative genetic support for different descriptive diagnostic categories, Nick Craddock, from Cardiff University, and colleagues examined genome-wide genetic association data on 1868 bipolar disorder patients and 2938 controls from the Wellcome Trust Case Control Consortium study.

The patients consisted of 1316 with bipolar I disorder, 279 with schizoaffective disorder bipolar type, 171 with bipolar II disorder, and 102 with manic disorder using the Research Diagnostic Criteria (RDC), and 1594 with bipolar I disorder, 98 with schizoaffective disorder bipolar type, 134 with bipolar II disorder, and 42 with bipolar disorder not otherwise specified using the DSM-IV criteria.

Using stringent quality filters, the researchers selected 276,122 singe nucleotide polymorphisms (SNPs) for analysis, determining association with bipolar disorder group versus controls, with the number of significantly associated independent SNPs used as a metric for the overall genetic signal.

The results demonstrated that, compared with controls, the category RDC schizoaffective disorder bipolar type had significantly more associated independent SNPs than the other categories, at nine hits versus ?5 hits.

Assessing the independent SNPs for the number of nearby SNPs in linkage disequilibrium with the index SNP, the team found an additional SNP on chromosome 16p13.3 (rs4786811) that had an acceptable clusterplot and a closely correlated SNP. Genes with ?1 associated SNP included B3GALTS, A2BP1, GABRB1, AUTS2, BSN, PTRG, GIRK2, and CDH12.

“Strong consideration is currently being given to abolishing the schizoaffective concept and category from the revisions of the official psychiatric diagnostic classifications,” the team writes in the British Journal of Psychiatry.

“This is unlikely to be unhelpful to the progress of psychiatric knowledge, given that it is emerging as a diagnostic entity that receives strong research support. We hope that psychiatry is moving towards the time when our patients can benefit from diagnostic concepts that are built on solid foundations of empirical biological evidence rather than being perched precariously on the shifting sands of expert opinion.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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Reduced hippocampal brain-derived neurotrophic factor precursor ([pro]BDNF) expression is common to both major depressive disorder (MDD) and bipolar disorder, UK investigators have discovered.

Brain-derived neurotrophic factor (BDNF) and (pro)BDNF are expressed in the developing and adult hippocampus, and other brain areas linked to schizophrenia and mood disorders. Several studies have also linked BDNF and BDNF polymorphisms to the pathophysiology of psychiatric illness.

To examine alterations in hippocampal levels of (pro)BDNF and receptor proteins TrkB and p75 and the impact of genetic variations on protein expression, C Toro, from Cranfield University, and colleagues studied anterior hippocampal sections from the Stanley Foundation Neuropathology Consortium.

The sections included samples from 15 patients with schizophrenia, 15 with MDD, 15 with bipolar disorder, and 13 age- and gender-matched controls. Immunoautoradiography was used to determine (pro)BDNF, TrkB, and p75 protein densities, and extracted DNA was genotyped for several single nucleotides (SNPs) in the BDNF, NTRK2, and NGFR genes.

All of the mood disorder groups had reduced (pro)BDNF density compared with controls. However, the overall differences were not significant, as any reductions in hippocampal layers were offset by an absence of change in the dentate gyrus.

Specifically, MDD patients had significantly reduced (pro)BDNF density in all three layers of the right hippocampus, while bipolar disorder patients had reductions in the right striatal oriens and striatal radiatum.

The results also show that bipolar disorder patients had bilateral reductions in p75 values compared with MDD, schizophrenia, and control groups in the hippocampus but not in the dentate gyrus. The differences were particularly marked compared with MDD patients.

The team also notes in the Journal of Psychiatric Research that, of the 31 SNPs studied, five were associated with changes in protein density across all hippocampal subregions that may affect hippocampal development.

Discussing the findings, they write: “It is tempting to speculate that a combined impairment of (pro)BDNF and p75 receptor function in bipolar disorder relates to the chronicity of depression rather than the occurrence of mania, however further larger-scale studies are necessary to test this theory.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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