Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor
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 heav...
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| Published in | Nature (London) Vol. 470; no. 7335; pp. 492 - 497 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
London
Nature Publishing Group UK
24.02.2011
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
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| 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.
A biomarker for stress disorders
In many species, pituitary adenylate cyclase-activating polypeptide (PACAP) is implicated in physiological responses to stress. A study of a sample of highly traumatized human females now shows that PACAP blood levels correlate with a diagnosis of post-traumatic stress disorder and with the degree of fear conditioning responses. One particular single-nucleotide polymorphism in the oestrogen response element of the receptor gene is closely associated with the condition, as is increased methylation of the receptor gene. Experiments in mice subjected to fear conditioning revealed increased transcription of both PACAP and receptor genes in the amygdala. These findings may set the stage for a novel biomarker for stress disorders and for explaining known sex differences in the occurrence of such conditions. |
|---|---|
| AbstractList | 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 ADCYAPl) 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. 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. 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. A biomarker for stress disorders In many species, pituitary adenylate cyclase-activating polypeptide (PACAP) is implicated in physiological responses to stress. A study of a sample of highly traumatized human females now shows that PACAP blood levels correlate with a diagnosis of post-traumatic stress disorder and with the degree of fear conditioning responses. One particular single-nucleotide polymorphism in the oestrogen response element of the receptor gene is closely associated with the condition, as is increased methylation of the receptor gene. Experiments in mice subjected to fear conditioning revealed increased transcription of both PACAP and receptor genes in the amygdala. These findings may set the stage for a novel biomarker for stress disorders and for explaining known sex differences in the occurrence of such conditions. 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.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. 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. [PUBLICATION 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. |
| Audience | Academic |
| Author | Braas, Karen M. Ressler, Kerry J. Binder, Elisabeth B. Jovanovic, Tanja Ramirez, Manuel Kerley, Kimberly Smith, Alicia K. May, Victor Hammack, Sayamwong E. Toufexis, Donna Engel, Anzhelika Norrholm, Seth D. Mahan, Amy Mercer, Kristina B. Myers, Amanda J. Bradley, Bekh Kilaru, Varun |
| AuthorAffiliation | 6 Department of Psychology, University of Vermont, Burlington, VT 8 Max Planck Institute of Psychiatry, Munich, Germany 2 Department of Psychiatry and Behavioral Sciences Emory University School of Medicine, Atlanta, GA 3 Atlanta VA Medical Center, Atlanta, GA 4 Yerkes National Primate Research Center, Atlanta, GA 7 Departments of Anatomy and Neurobiology and Pharmacology, University of Vermont College of Medicine, Burlington, VT 1 Howard Hughes Medical Institute, Chevy Chase, MD 5 University of Miami, Miller School of Medicine, Miami, FL |
| AuthorAffiliation_xml | – name: 8 Max Planck Institute of Psychiatry, Munich, Germany – name: 4 Yerkes National Primate Research Center, Atlanta, GA – name: 7 Departments of Anatomy and Neurobiology and Pharmacology, University of Vermont College of Medicine, Burlington, VT – name: 1 Howard Hughes Medical Institute, Chevy Chase, MD – name: 5 University of Miami, Miller School of Medicine, Miami, FL – name: 3 Atlanta VA Medical Center, Atlanta, GA – name: 2 Department of Psychiatry and Behavioral Sciences Emory University School of Medicine, Atlanta, GA – name: 6 Department of Psychology, University of Vermont, Burlington, VT |
| Author_xml | – sequence: 1 givenname: Kerry J. surname: Ressler fullname: Ressler, Kerry J. email: kressle@emory.edu organization: Howard Hughes Medical Institute, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Yerkes National Primate Research Center – sequence: 2 givenname: Kristina B. surname: Mercer fullname: Mercer, Kristina B. organization: Howard Hughes Medical Institute – sequence: 3 givenname: Bekh surname: Bradley fullname: Bradley, Bekh organization: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta VA Medical Center – sequence: 4 givenname: Tanja surname: Jovanovic fullname: Jovanovic, Tanja organization: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine – sequence: 5 givenname: Amy surname: Mahan fullname: Mahan, Amy organization: Yerkes National Primate Research Center – sequence: 6 givenname: Kimberly surname: Kerley fullname: Kerley, Kimberly organization: Howard Hughes Medical Institute – sequence: 7 givenname: Seth D. surname: Norrholm fullname: Norrholm, Seth D. organization: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta VA Medical Center – sequence: 8 givenname: Varun surname: Kilaru fullname: Kilaru, Varun organization: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine – sequence: 9 givenname: Alicia K. surname: Smith fullname: Smith, Alicia K. organization: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine – sequence: 10 givenname: Amanda J. surname: Myers fullname: Myers, Amanda J. organization: University of Miami, Miller School of Medicine – sequence: 11 givenname: Manuel surname: Ramirez fullname: Ramirez, Manuel organization: University of Miami, Miller School of Medicine – sequence: 12 givenname: Anzhelika surname: Engel fullname: Engel, Anzhelika organization: University of Miami, Miller School of Medicine – sequence: 13 givenname: Sayamwong E. surname: Hammack fullname: Hammack, Sayamwong E. organization: Department of Psychology, University of Vermont – sequence: 14 givenname: Donna surname: Toufexis fullname: Toufexis, Donna organization: Yerkes National Primate Research Center, Department of Psychology, University of Vermont – sequence: 15 givenname: Karen M. surname: Braas fullname: Braas, Karen M. organization: Departments of Anatomy and Neurobiology and Pharmacology, University of Vermont College of Medicine – sequence: 16 givenname: Elisabeth B. surname: Binder fullname: Binder, Elisabeth B. organization: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Max Planck Institute of Psychiatry – sequence: 17 givenname: Victor surname: May fullname: May, Victor organization: Departments of Anatomy and Neurobiology and Pharmacology, University of Vermont College of Medicine |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23873067$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/21350482$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | 631/378/1689/1830 692/420/2489/144 692/53 Adult and adolescent clinical studies Amygdala - metabolism Animals Anxiety disorders. Neuroses Biological and medical sciences Causes of Conditioning, Classical - physiology CpG Islands - genetics DNA Methylation Estrogens - metabolism Estrogens - pharmacology Fear - physiology Female Females Gene expression Gene Expression Regulation - drug effects Genetic aspects Genetic Association Studies Genetic Predisposition to Disease - genetics Humanities and Social Sciences Humans Male Males Medical sciences Mice multidisciplinary Physiological aspects Pituitary Adenylate Cyclase-Activating Polypeptide - blood Pituitary Adenylate Cyclase-Activating Polypeptide - chemistry Polymorphism, Single Nucleotide - genetics Polypeptides Post traumatic stress disorder Psychological aspects Psychology. Psychoanalysis. Psychiatry Psychopathology. Psychiatry Rats Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I - genetics Response Elements - genetics RNA, Messenger - analysis RNA, Messenger - biosynthesis RNA, Messenger - genetics Rodents Science Science (multidisciplinary) Septal Nuclei - drug effects Septal Nuclei - metabolism Sex Characteristics Stress Disorders, Post-Traumatic - blood Stress Disorders, Post-Traumatic - genetics Stress Disorders, Post-Traumatic - physiopathology Stress Disorders, Post-Traumatic - psychology Studies |
| Title | Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor |
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