Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP/PAC1 receptor pathway has a role in human psychological stress responses, such as posttraumatic stress disorder (PTSD). In heavily traumatized subjects, we find a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females (N=64, replication N=74,
p<0.005)
. Using a tag-SNP genetic approach (44 single nucleotide polymorphisms, SNPs) spanning the PACAP (
ADCYAP1
) and PAC1 (
ADCYAP1R1
) genes, we find a sex-specific association with PTSD. rs2267735, a SNP in a putative estrogen response element within
ADCYAP1R1,
predicts PTSD diagnosis and symptoms in females only (combined initial and replication samples: N=1237;
p<2x10
−
5
). This SNP also associates with fear discrimination and with
ADCYAP1R1
mRNA expression. Methylation of
ADCYAP1R1
is also associated with PTSD (
p < 0.001
). Complementing these human data,
ADCYAP1R1
mRNA is induced with fear conditioning or estrogen replacement in rodent models. These data suggest that perturbations in the PACAP/PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via estrogen regulation of
ADCYAP1R1
. PACAP levels and
ADCYAP1R1
SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.
