Multiple mechanisms may differentially mediate sex differences in mood and anxiety disorders. This presentation will examine two different genetics and neuroimaging studies which demonstrate differential sex-specific associations with posttraumatic stress disorder (PTSD) symptoms.

          We examined 44 single nucleotide polymorphisms (SNPs) spanning the pituitary adenylate cyclase activating peptide (PACAP, encoded by ADCYAP1) and its receptor (encoded by ADCYAP1R1) genes in >1200 individuals, demonstrating a sex-specific association with PTSD.  A single SNP in a putative estrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only.  

            Recently we have expanded these data with a replications further examining the effects, and  have also examined the effects of this genotype on brain activity.   49 women who experienced significant lifetime trauma participated in a functional MRI task involving passive viewing of threatening and neutral face stimuli. Analyses focused on the amygdala and hippocampus, regions that play central roles in the pathophysiology of PTSD. The risk genotype was associated with increased reactivity of the amygdala and hippocampus to threat stimuli and decreased functional connectivity between the amygdala and hippocampus.

          Separately, we have examined a non-synonymous, SNP in the gene coding for steroid 5-α-reductase type 2 (SRD5A2), which is associated with reduced conversion of testosterone to dihydrotestosterone (DHT) subjects. We found a significant sex-dependent effect of genotype in male but not female subjects on PTSD symptoms (n>1200). 

             We thus demonstrate different examples of sex-specific effects in genetic association and neuroimaging studies in which trauma exposure is associated with differential levels of posttraumatic stress or depression symptoms in males vs. females. It is important to appreciate that there are likely many different possible mechanisms which may mediate different sex-specific effects, and that estrogen, testosterone, and their metabolites, along with social and trauma differences may all be processed via different molecular pathways.