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Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor

Nature volume 470, pages 492–497 (2011)Cite this article

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An Addendum to this article was published on 31 August 2011

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.

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Figure 1: PACAP blood levels predict PTSD symptoms in females.
Figure 2: Genetic association of PAC1 receptor ( ADCYAP1R1 ) with PTSD.
Figure 3: Association of ADCYAP1R1 rs2267735 with PTSD symptoms and physiological fear responses.
Figure 4: ADCYAP1R1 methylation and mRNA expression.
Figure 5: Regulation of Adcyap1r1 and Adcyap1 mRNA in rodent models.

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Acknowledgements

This work was primarily supported by NIH grant MH071537 (K.J.R.), as well as DA019624 (K.J.R.) and HD27468 (V.M.). Support was also received from Emory and Grady Memorial Hospital General Clinical Research Center, NIH National Centers for Research Resources (M01RR00039 and P20RR16435), the American Foundation for Suicide Prevention (B.B.) and the Burroughs Wellcome Fund (K.J.R.). RNA samples were run using the Oncogenomics Core Facility at University of Miami. A.J.M. is supported by The National Institute on Aging (AG034504). We thank J.F. Cubells, Y. Tang and K. Conneely for discussions. We thank the Grady Trauma Project, including C.F. Gillespie, A. Schwartz, A. Wingo, D.A. Gutman and T. Weiss for medical support; A. Graham, A. Brown, J. Phifer, D. Crain, A. Kamkwalala, J. Poole, D. Cross, N. Fani and A. Smith for clinical research support; and K. Schutz, E. Reiser and C. Fitzgerald for molecular/genetics technical support. Methylation chip assays were performed by the Emory University Biomarkers Service Center.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Chevy Chase, 20815, Maryland, USA

    Kerry J. Ressler, Kristina B. Mercer & Kimberly Kerley

  2. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, 30322, Georgia, USA

    Kerry J. Ressler, Bekh Bradley, Tanja Jovanovic, Seth D. Norrholm, Varun Kilaru, Alicia K. Smith & Elisabeth B. Binder

  3. Atlanta VA Medical Center, Atlanta, 30033, Georgia, USA

    Bekh Bradley & Seth D. Norrholm

  4. Yerkes National Primate Research Center, Atlanta, 30329, Georgia, USA

    Kerry J. Ressler, Amy Mahan & Donna Toufexis

  5. University of Miami, Miller School of Medicine, Miami, 33136, Florida, USA

    Amanda J. Myers, Manuel Ramirez & Anzhelika Engel

  6. Department of Psychology, University of Vermont, Burlington, 05401, Vermont, USA

    Sayamwong E. Hammack & Donna Toufexis

  7. Departments of Anatomy and Neurobiology and Pharmacology, University of Vermont College of Medicine, Burlington, 05401, Vermont, USA

    Karen M. Braas & Victor May

  8. Max Planck Institute of Psychiatry, Munich, 80804, Germany

    Elisabeth B. Binder

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Contributions

K.J.R. designed the initial experiments and wrote the initial version of the paper. K.J.R., B.B. and V.M. organized collaborations, obtained funding, supervised data collection and analyses, and revised the paper. K.B.M., K.K. and E.B.B. performed the genetics experiments and analyses on the primary, replication and GAIN cohorts, and revised the paper. T.J. and S.D.N. performed and supervised the human physiology studies and revised the paper. V.K. and A.K.S. performed and supervised the methylation studies and revised the paper. A.M. and K.J.R. performed and supervised the rodent fear conditioning and related RT–PCR analysis. D.T., S.E.H. and V.M. performed and supervised the oestrogen replacement studies and related RT–PCR analyses, and assisted with paper revisions. A.J.M., M.R. and A.E. performed and supervised the human mRNA expression analyses and the Alzheimer’s disease gene association studies. K.M.B. and V.M. performed and supervised the PACAP38 radioimmunoassays and related data analyses.

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Correspondence to Kerry J. Ressler.

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Ressler, K., Mercer, K., Bradley, B. et al. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature 470, 492–497 (2011). https://doi.org/10.1038/nature09856

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