title: Functional evaluation of a PTSD-associated genetic variant: estradiol regulation and ADCYAP1R1.
abstract: Posttraumatic stress disorder (PTSD) affects 5-10% percent of the US adult population with a higher prevalence among women compared with men. Although it remains unclear how biological sex associates with susceptibility to PTSD, one mechanism may involve a role for estrogen in a gene by environment interaction. We previously demonstrated a sex-dependent association between the pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1) and PTSD, where carriers of a C allele at single-nucleotide polymorphism (SNP) rs2267735 within the PAC1 receptor gene (ADCYAP1R1) have increased symptoms of PTSD. This SNP is located within a predicted estrogen response element (ERE), which regulates gene transcription when bound to estradiol (E2) activated estrogen receptor alpha (ERα). In the current study, we examined E2 regulation of ADCYAP1R1 in vitro, in cell culture, and in vivo in mice and humans. We find in mice that fear conditioning and E2 additively increase ADCYAP1R1 expression. In vitro, we show that E2/ERα binds to the ADCYAP1R1 ERE, with less efficient binding to an ERE containing the C allele of rs2267735. In women with low serum E2, the CC genotype associates with lower ADCYAP1R1 expression, which further associates with higher PTSD symptoms. These findings lead to a model in which E2 induces the expression of ADCYAP1R1 through binding of ERα at the ERE as an adaptive response to stress. Inhibition of E2/ERα binding to the ERE containing the rs2267735 risk allele results in reduced expression of ADCYAP1R1, diminishing estrogen regulation as an adaptive stress response and increasing risk for PTSD.
authors.affiliation: Department of Psychiatry and Behavioral Science, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: K B
authors.initials: KB
authors.lastname: Mercer
authors.affiliation: Department of Psychiatry and Behavioral Science, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Dias
authors.affiliation: Department of Psychiatry and Behavioral Science, Emory University School of Medicine, Atlanta, GA, USA.|GeneTAG Technology, Inc., Atlanta, GA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Shafer
authors.affiliation: McLean Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Maddox
authors.affiliation: Department of Epidemiology, Emory University, Rollins School of Public Health, Atlanta, GA, USA.|Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Mulle
authors.affiliation: GeneTAG Technology, Inc., Atlanta, GA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Hu
authors.affiliation: McLean Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Walton
authors.affiliation: Department of Psychiatry and Behavioral Science, Emory University School of Medicine, Atlanta, GA, USA.|McLean Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Ressler
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003214:Conditioning, Classical / Q000502:physiology; D004958:Estradiol / Q000502:physiology*; D005239:Fear / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006580:Genetic Carrier Screening; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D051379:Mice; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000235:genetics*; D012737:Sex Factors; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics* / Q000503:physiopathology
chemical_list: C495503:ADCYAP1R1 protein, human; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D004958:Estradiol