Sage E Hawn1, Christina M Sheerin2, Mackenzie J Lind2, Terrell A Hicks3, Marisa E Marraccini4, Kaitlin Bountress2, Silviu-Alin Bacanu2, Nicole R Nugent5, Ananda B Amstadter6. 1. Department of Psychiatry, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA; Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: hawnse@vcu.edu. 2. Department of Psychiatry, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA. 3. Department of Psychiatry, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA; Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA. 4. School of Education, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 5. Bradley-Hasbro Children's Research Center, Rhode Island Hospital, Providence, RI, USA; Departments of Psychiatry and Human Behavior and Pediatrics, Alpert Medical School of Brown University, Providence, RI, USA. 6. Department of Psychiatry, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
Abstract
BACKGROUND: Twin studies have demonstrated that both genetic and environmental factors influence risk for posttraumatic stress disorder (PTSD), and there is some evidence supporting the interplay of genes and environment (GxE). Many GxE studies within the PTSD literature have focused on genes implicated in the stress response system, such as FK506 binding protein 51 (FKBP5). Given inconsistencies across GxE literature as a whole, a meta-analysis to synthesize results is warranted. METHODS: Studies were identified through PubMed and PsycINFO. A meta-analysis was conducted using a random effects model in the MAc package in R. Heterogeneity of the effect size distribution was examined with Cochran's Q statistic. A Simes procedure was used to test the gene-level GxE effect for FKBP5 interacting with trauma. RESULTS: A significant gene-level GxE gene effect was demonstrated for FKBP5 when pooled across all four examined variants (rs1360780, rs3800373, rs9296158, rs9470080) when interacting with trauma exposure on PTSD. Significant large GxE effect sizes were also found for each independent variant. There was no evidence for heterogeneity of variance. LIMITATIONS: Limitations include reduced power for detecting variability across moderators, potential bias due to failure of meta-analyzed studies to account for two-way covariate x gene and covariate x environment influences, and a high false discovery rate that is characteristic of GxE analyses. CONCLUSIONS: This is the first study to quantify an overall gene-level effect of FKBP5 in a GxE analysis of PTSD, evidence which may be used to address current issues in the FKBP5 GxE literature (e.g., disparate variants, low sample sizes and power), as well as inform follow-up functional research.
BACKGROUND: Twin studies have demonstrated that both genetic and environmental factors influence risk for posttraumatic stress disorder (PTSD), and there is some evidence supporting the interplay of genes and environment (GxE). Many GxE studies within the PTSD literature have focused on genes implicated in the stress response system, such as FK506 binding protein 51 (FKBP5). Given inconsistencies across GxE literature as a whole, a meta-analysis to synthesize results is warranted. METHODS: Studies were identified through PubMed and PsycINFO. A meta-analysis was conducted using a random effects model in the MAc package in R. Heterogeneity of the effect size distribution was examined with Cochran's Q statistic. A Simes procedure was used to test the gene-level GxE effect for FKBP5 interacting with trauma. RESULTS: A significant gene-level GxE gene effect was demonstrated for FKBP5 when pooled across all four examined variants (rs1360780, rs3800373, rs9296158, rs9470080) when interacting with trauma exposure on PTSD. Significant large GxE effect sizes were also found for each independent variant. There was no evidence for heterogeneity of variance. LIMITATIONS: Limitations include reduced power for detecting variability across moderators, potential bias due to failure of meta-analyzed studies to account for two-way covariate x gene and covariate x environment influences, and a high false discovery rate that is characteristic of GxE analyses. CONCLUSIONS: This is the first study to quantify an overall gene-level effect of FKBP5 in a GxE analysis of PTSD, evidence which may be used to address current issues in the FKBP5 GxE literature (e.g., disparate variants, low sample sizes and power), as well as inform follow-up functional research.
Authors: Kerry J Ressler; Sabina Berretta; Vadim Y Bolshakov; Isabelle M Rosso; Edward G Meloni; Scott L Rauch; William A Carlezon Journal: Nat Rev Neurol Date: 2022-03-29 Impact factor: 44.711
Authors: Christina M Sheerin; Mackenzie J Lind; Kaitlin E Bountress; Marisa E Marraccini; Ananda B Amstadter; Silviu-Alin Bacanu; Nicole R Nugent Journal: J Trauma Stress Date: 2020-03-26
Authors: Stefan Wuchty; Amanda J Myers; Manuel Ramirez-Restrepo; Matthew Huentelman; Ryan Richolt; Felicia Gould; Philip D Harvey; Vasiliki Michopolous; Jennifer S Steven; Aliza P Wingo; Adriana Lori; Jessica L Maples-Keller; Alex O Rothbaum; Tanja Jovanovic; Barbara O Rothbaum; Kerry J Ressler; Charles B Nemeroff Journal: Mol Psychiatry Date: 2021-05-07 Impact factor: 15.992
Authors: Suzanne L Pineles; Yael I Nillni; Graziano Pinna; Andrea Webb; Kimberly A Arditte Hall; Jennifer R Fonda; John Irvine; Matthew W King; Richard L Hauger; Patricia A Resick; Scott P Orr; Ann M Rasmusson Journal: Neurobiol Stress Date: 2020-05-15
Authors: Christina M Sheerin; Laurel V Kovalchick; Cassie Overstreet; Lance M Rappaport; Vernell Williamson; Vladimir Vladimirov; Kenneth J Ruggiero; Ananda B Amstadter Journal: Brain Sci Date: 2019-06-20