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 x 10(-5)). A global haplotype test of the six SNPs was likewise significant (p = 3.7 x 10(-6)). No single SNP or haplotype accounted for all of the association observed.


CONCLUSIONS
These preliminary results suggest a strong, gender-specific association between variation at the CREB1 locus and anger expression in MDD.
Perlis
Roy H
RH
Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. rperlis@partners.org
Purcell
Shaun
S
Fagerness
Jesen
J
Cusin
Cristina
C
Yamaki
Lesley
L
Fava
Maurizio
M
Smoller
Jordan W
JW
D000328:Adult; D000786:Anger / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D003865:Major Depressive Disorder / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010555:Personality Inventory; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012737:Sex Factors
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein