rs2267735

Gene-based meta-analysis of 24 studies examining hypothalamic-pituitary-adrenal (HPA) axis genes and posttraumatic stress disorder (PTSD) risk. SNP-level meta-analyses identified two variants nominally associated with PTSD after multiple testing correction: rs9296158 in FKBP5 (p = 0.001) and rs258747 in NR3C1 (p = 0.001). Gene-level meta-analyses showed significant associations with PTSD for NR3C1 (p = 0.003), CRHR1 (p = 0.017), and FKBP5 (p = 0.011), with NR3C1 and FKBP5 showing robust signals in sensitivity analyses.

A replication and meta-analysis study demonstrating that rs2267735 in ADCYAP1R1 (PAC1 receptor gene) shows a significant genotype × trauma interaction predicting PTSD symptom severity in highly traumatized African-American females (N=1424, P<0.0001), with the C allele associated with increased PTSD severity at higher trauma loads, but no main effect of genotype. The interaction remained significant after controlling for multiple covariates including age, income, substance abuse, depression, and childhood abuse.

This candidate gene association study of 495 adult females from the Detroit Neighborhood Health Study examined whether ADCYAP1R1 genotype (rs2267735) interacts with childhood maltreatment (CM) to predict PTSD and depression. While no significant main effects of rs2267735 genotype were observed, a significant ADCYAP1R1 × CM interaction was found for PTSD (17% increased odds per unit CM score for C-allele carriers), with carriers of the C-allele showing enhanced risk among women exposed to CM. No significant gene-environment interaction was observed for depression.