Clinical and Genetic Dissection of Anger Expression and CREB1 Polymorphisms in Major Depressive Disorder

BackgroundAnger and irritability are prominent in a subset of individuals with major depressive disorder (MDD). Phosphorylation of the transcription factor cyclic adenosine monophosphate (cAMP) Response Element Binding Protein (CREB) has been associated with aggression or reward/aversion in rodents, and markers near CREB1 have been linked to MDD. Therefore, we examined the association between CREB1 polymorphisms and anger expression in MDD.MethodsA clinical sample of 94 Caucasian outpatients with MDD (42 male, 52 female) completed the Spielberger State-Trait Anger Expression Inventory. We examined six tagging single nucleotide polymorphisms (SNPs) spanning CREB1 and flanking regions for association with a summary measure of frequency and intensity of anger expression. We also introduced a novel statistical method to dissect the independent effect of individual SNPs and haplotypes.ResultsFor the sample as a whole, one of six SNPs tested was significantly associated with anger expression (empirical p = .003). Among the male subsample, this association was particularly marked (empirical p = 8 × 10−5). A global haplotype test of the six SNPs was likewise significant (p = 3.7 × 10−6). No single SNP or haplotype accounted for all of the association observed.ConclusionThese preliminary results suggest a strong, gender-specific association between variation at the CREB1 locus and anger expression in MDD.