Individuals with variations in gamma-amino butyric acid A (GABA_A) receptor genes may be more susceptible to the bipolar disorder phenotype schizoaffective disorder, bipolar type (SABP), study findings suggest.

Variation in these genes was not associated with any other bipolar disorder phenotype, however.

Nick Craddock, from Cardiff University in Wales, UK, and colleagues note that unknown biological validity of current bipolar disorder phenotypes makes it difficult to implicate specific genes or systems in the risk for bipolar disorder, despite compelling evidence for a substantial genetic contribution.

In the recent Wellcome Trust Case Control consortium genome-wide association analysis of bipolar disorder, comprising 1868 patients and 2938 controls, the polymorphisms most strongly associated with the condition lay within the gene encoding the GABA_A receptor ?1 subunit, or GABRB1.

The researchers investigated this association further to determine whether it is specific to certain diagnostic subsets and whether other GABA_A receptor genes are also involved.

Using logistic regression analysis they found that, of 11 clinical phenotypic subsets considered, a subset of 279 bipolar patients who met the Research Diagnostic Criteria for SABP showed the strongest evidence for an association with the GABRB1 risk allele, at the index single nucleotide polymorphism rs7680321, with an odds ratio of 1.80.

By contrast, the remaining 1589 patients with BD had an attenuated association signal for this polymorphism, at an odds ratio of 1.26.

Testing a further 18 genes from the GABA_A receptor gene family in the subset of patients with SABP, the researchers found that five ??” GABRB1, GABRA5, GABRB3, GABRA4, and GABRR3 ??” were significantly associated with the risk for SABP independent of the index signal.

“In our sample, estimates of population attributable fraction were in the range 10??”20% for several of these risk alleles,” note Craddock et al in the journal Molecular Psychiatry.

“This suggests that variation at GABA_A receptor genes make an important contribution to the burden of this disease phenotype in the population.”

The researchers conclude that patients with SABP seem to be more biologically homogenous than bipolar disorder patients as a whole.

Their findings also help explain some of the common comorbidity between bipolar disorder and alcohol abuse, anxiety states, and panic episodes, as GABAergic transmission is strongly implicated in all of them.

“Indeed, it may soon be possible to start developing diagnostic classifications that group disorders together according to underlying pathogenesis,” says the team. “Such a move is likely to be beneficial for etiological research as well as clinical management and would signal a shift from the current situation of a purely descriptive approach.”

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; 2010

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