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

Background: Anger 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. Methods: A 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. Results: For 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. Conclusion: These preliminary results suggest a strong, gender-specific association between variation at the CREB1 locus and anger expression in MDD.