We have recently found higher circulating levels of pituitary adenylate cyclase-activating polypeptide (PACAP) associated with posttraumatic stress disorder (PTSD) symptoms in a highly traumatized cohort of women but not men. Furthermore, a single nucleotide polymorphism in the PACAP receptor gene ADCYAP1R1, adenylate cyclase activating polypeptide 1 receptor type 1, was associated with individual differences in PTSD symptoms and psychophysiological markers of fear and anxiety. The current study outlines an investigation of individual differences in brain function associated with ADCYAP1R1 genotype. Forty-nine women who had experienced moderate to high levels of 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 and are known to have high densities of PACAP receptors. 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. The findings indicate that the PACAP system modulates medial temporal lobe function in humans. Individual differences in ADCYAP1R1 genotype may contribute to dysregulated fear circuitry known to play a central role in PTSD and other anxiety disorders.fMRI | emotion | intermediate phenotype | single nucleotide polymorphism P osttraumatic stress disorder (PTSD) is an anxiety disorder estimated to affect 7% of the population (1), with symptoms that are highly debilitating and associated with a range of major physical health conditions (2, 3). PTSD disproportionally affects women over men (1, 4), and mechanisms for this sex difference have not yet been defined. We recently identified a single nucleotidepolymorphism (SNP) in the gene coding for the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor (ADCYAP1R1, adenylate cyclase activating polypeptide 1 receptor type 1) that predicts PTSD in women and not men (5-9). This SNP, rs2267735, is located on a canonical estrogen response element, indicating that estrogen levels may influence expression of the receptor. The ADCYAP1R1 polymorphism has been shown to predict exaggerated arousal responses characteristic of PTSD in autonomic psychophysiology (5, 10), but no study has yet examined the extent to which this polymorphism influences fear responses in the human brain. The current study tests the hypothesis that ADCYAP1R1 polymorphism influences brain regions that underlie emotional arousal, using functional MRI (fMRI) in a sample of women who have experienced civilian trauma.PTSD symptom clusters include hyperarousal, reexperiencing, avoidance, and numbing (11). Recently, evidence has accumulated to support the idea that hyperarousal is predictive of PTSD after trauma, whereas other symptoms are products of the disorder (12). In particular, pretrauma reactivity of the amygdalaa brain region responsible for coordinating and mainta...

Background Civilian posttraumatic stress disorder (PTSD) and combat PTSD are major public health concerns. Although a number of psychosocial risk factors have been identified related to PTSD risk, there are no accepted, robust biological predictors that identify who will develop PTSD or who will respond to early intervention following trauma. We wished to examine whether genetic risk for PTSD can be mitigated with an early intervention. Method 65 emergency department patients recruited in 2009–2010 at Grady Memorial Hospital in Atlanta, Georgia, who met criterion A of DSM-IV PTSD received either 3 sessions of an exposure intervention, beginning in the emergency department shortly after trauma exposure or assessment only. PTSD symptoms were assessed 4 and 12 weeks after trauma exposure. A composite additive risk score was derived from polymorphisms in 10 previously identified genes associated with stress-response (ADCYAP1R1, COMT, CRHR1, DBH, DRD2, FAAH, FKBP5, NPY, NTRK2, and PCLO), and gene x treatment effects were examined. The intervention included 3 sessions of imaginal exposure to the trauma memory and additional exposure homework. The primary outcome measure was the PTSD Symptom Scale-Interview Version or DSM-IV–based PTSD diagnosis in patients related to genotype and treatment group. Results A gene x intervention x time effect was detected for individual polymorphisms, in particular the PACAP receptor, ADCYAP1R1, as well as with a combined genotype risk score created from independent SNP markers. Subjects who did not receive treatment had higher symptoms than those who received intervention. Furthermore, subjects with the “risk” genotypes who did not receive intervention had higher PTSD symptoms compared to those with the “low-risk” or “resilience” genotypes or those who received intervention. Additionally, PTSD symptoms correlated with level of genetic risk at week 12 (P < .005) in the assessment-only group, but with no relationship in the intervention group, even after controlling for age, sex, race, education, income, and childhood trauma. Using logistic regression, the number of risk alleles was significantly associated with likelihood of PTSD diagnosis at week 12 (P < .05). Conclusions This pilot prospective study suggests that combined genetic variants may serve to predict those most at risk for developing PTSD following trauma. A psychotherapeutic intervention initiated in the emergency department within hours of the trauma may mitigate this risk. The role of genetic predictors of risk and resilience should be further evaluated in larger, prospective intervention and prevention trials. Trial Registration ClinicalTrials.gov identifier: NCT00895518

Alterations in the microarchitecture of the posterior cingulum (PC), a white matter tract proximal to the hippocampus that facilitates communication between the entorhinal and cingulate cortices, have been observed in individuals with psychiatric disorders, such as depression and post-traumatic stress disorder (PTSD). PC decrements may be a heritable source of vulnerability for the development of affective disorders; however, genetic substrates for these white matter abnormalities have not been identified. The FKBP5 gene product modulates glucocorticoid receptor function and has been previously associated with differential hippocampal structure, function, and affect disorder risk. Thus, FKBP5 is an attractive genetic target for investigations of PC integrity. We examined associations between PC integrity, measured through diffusion tensor imaging (DTI) and fractional anisotropy (FA; an index of white matter integrity), and polymorphisms in the FKBP5 SNP rs1360780 in a sample of 82 traumatized female civilians. Findings indicated that, compared with individuals without this allele, individuals who carried two 'risk' alleles for this FKBP5 SNP (T allele; previously associated with mood and anxiety disorder risk) demonstrated significantly lower FA in the left PC, even after statistically controlling for variance associated with age, trauma exposure, and PTSD symptoms. These data suggest that specific allelic variants for an FKBP5 polymorphism are associated with decrements in the left PC microarchitecture. These white matter abnormalities may be a heritable biological marker that indicates increased vulnerability for the development of psychiatric disorders, such as PTSD.