title: Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.
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 post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen 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 oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. kressle@emory.edu
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
authors.forename: Kristina B
authors.initials: KB
authors.lastname: Mercer
authors.forename: Bekh
authors.initials: B
authors.lastname: Bradley
authors.forename: Tanja
authors.initials: T
authors.lastname: Jovanovic
authors.forename: Amy
authors.initials: A
authors.lastname: Mahan
authors.forename: Kimberly
authors.initials: K
authors.lastname: Kerley
authors.forename: Seth D
authors.initials: SD
authors.lastname: Norrholm
authors.forename: Varun
authors.initials: V
authors.lastname: Kilaru
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Smith
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Myers
authors.forename: Manuel
authors.initials: M
authors.lastname: Ramirez
authors.forename: Anzhelika
authors.initials: A
authors.lastname: Engel
authors.forename: Sayamwong E
authors.initials: SE
authors.lastname: Hammack
authors.forename: Donna
authors.initials: D
authors.lastname: Toufexis
authors.forename: Karen M
authors.initials: KM
authors.lastname: Braas
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.forename: Victor
authors.initials: V
authors.lastname: May
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000818:Animals; D003214:Conditioning, Classical / Q000502:physiology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D005239:Fear / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000097:blood* / Q000737:chemistry; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000235:genetics*; D020218:Response Elements / Q000235:genetics; D012686:Septal Nuclei / Q000187:drug effects / Q000378:metabolism; D012727:Sex Characteristics; D013313:Stress Disorders, Post-Traumatic / Q000097:blood* / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology
chemical_list: C495401:ADCYAP1 protein, human; C495503:ADCYAP1R1 protein, human; C495504:Adcyap1r1 protein, mouse; D004967:Estrogens; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I