Genetic markers for PTSD risk and resilience among survivors of the World Trade Center attacks

Issue title: Molecular Biology of Post Traumatic Stress Disorder

Article type: Research Article

Authors: Sarapas, Casey | Cai, Guiqing | Bierer, Linda M. | Golier, Julia A. | Galea, Sandro | Ising, Marcus | Rein, Theo | Schmeidler, James | Müller-Myhsok, Bertram | Uhr, Manfred | Holsboer, Florian | Buxbaum, Joseph D. | Yehuda, Rachel

Affiliations: Department of Psychology, University of Illinois at Chicago, Chicago, IL, USA | Laboratory of Molecular Neuropsychiatry, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA | Traumatic Stress Studies Division, Mount Sinai School of Medicine and James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA | Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA | Max Planck Institute for Psychiatry, Munich, Germany

Note: [] Corresponding author: Rachel Yehuda, Ph.D., 526 OOMH PTSD 116/A, James J. Peters Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY 10458, USA. Tel.: +1 718 741 4000 ext. 6567; Fax: +1 718 741 4775; E-mail: rachel.yehuda@va.gov

Abstract: We have previously reported the differential expression of 17 probe sets in survivors of the 9/11 attacks with current posttraumatic stress disorder (PTSD) compared to similarly exposed survivors with no lifetime PTSD. The current study presents an expanded analysis of these subjects, including genotype at FKBP5, a modulator of glucocorticoid receptor (GR) sensitivity. It includes data from additional subjects who developed PTSD following 9/11 but then recovered, distinguishing expression profiles associated with risk for developing PTSD, resilience, and symptom recovery. 40 Caucasians (20 with and 20 without PTSD, matched for exposure, age, and gender) were selected from a population-representative sample of persons exposed to the 9/11 attacks from which longitudinal data had been collected in four previous waves. Whole blood gene expression and cortisol levels were obtained and genome-wide gene expression was analyzed. 25 probe sets were differentially expressed in PTSD. Identified genes were generally involved in hypothalamic-pituitary-adrenal axis, signal transduction, or in brain and immune cell function. STAT5B, a direct inhibitor of GR, and nuclear factor I/A, both showed reduced expression in PTSD. Comparison of lifetime versus current PTSD identified overlapping genes with altered expression suggesting enduring markers, while some markers present only in current PTSD may reflect state measures. As a follow-up, direct comparisons of expression in current PTSD, lifetime-only PTSD, and control groups identified FKBP5 and MHC Class II as state markers, and also identified several trait markers. An analysis of indirect effects revealed that homozygosity for any of 4 PTSD risk-related polymorphisms at FKBP5 predicted FKBP5 expression, which mediated indirect effects of genotype on plasma cortisol and PTSD severity.

Keywords: Stress disorders, post-traumatic, gene expression, genotype, FKBP5 protein, human, cortisol, September 11 terrorist attacks, childhood trauma

DOI: 10.3233/DMA-2011-0764

Journal: Disease Markers, vol. 30, no. 2-3, pp. 101-110, 2011