Lithium response and genetic variation in the CREB family of genes

Bipolar disorder (BD) is a severe psychiatric disorder that affects 1% of the population. Recently, there have been many attempts to identify specific genes that are involved in BD; however, the task of finding susceptibility genes is not easy due to the complexity of the disorder. Since lithium (Li) has been used for over 40 years now as an effective prophylactic agent and response to Li treatment seems to be, at least in part, genetically determined, classification according to Li response is a manner through which more homogeneous populations can be obtained for investigation. It has previously been suggested that Li exerts an effect on signal transduction pathways, such as the cyclic adenosine monophosphate (cAMP) pathway. We carried out an association study of BD with CREB1, CREB2 and CREB3 genes, located at ch 2q32.3-q34, 22q13.1 and 9pter-p22.1, respectively. A total of three promoter single nucleotide polymorphisms (SNP), 14 SNPs in the UTR, 6 exonic and 15 intronic SNPs were investigated for their frequency and haplotype distribution in a BD sample of 180 lithium responders and 69 nonresponders and 127 controls using a SNaPshot multiplex reaction from Applied Biosystems, a modified fluorescent single base pair extension procedure. Following correction for multiple testing, our results suggest that the CREB1-1H SNP (G/A change, P < 0.002) and the CREB1-7H SNP (T/C change, P < 0.002) may be associated with BD and/or lithium response.