Danielle R Sullivan1, Filomene G Morrison2, Erika J Wolf2, Mark W Logue3, Catherine B Fortier4, David H Salat5, Jennifer R Fonda6, Annjanette Stone7, Steven Schichman7, William Milberg4, Regina McGlinchey4, Mark W Miller2. 1. National Center for PTSD, VA Boston Healthcare System, Boston, MA, United States; Department of Psychiatry, Boston University School of Medicine, Boston, MA, United States. Electronic address: drsulliv@bu.edu. 2. National Center for PTSD, VA Boston Healthcare System, Boston, MA, United States; Department of Psychiatry, Boston University School of Medicine, Boston, MA, United States. 3. National Center for PTSD, VA Boston Healthcare System, Boston, MA, United States; Biomedical Genetics, Boston University School of Medicine, Boston, MA, United States; Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States. 4. Translational Research Center for TBI and Stress Disorders (TRACTS) and Geriatric Research, Educational and Clinical Center (GRECC), VA Boston Healthcare System, Boston, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States. 5. Translational Research Center for TBI and Stress Disorders (TRACTS) and Geriatric Research, Educational and Clinical Center (GRECC), VA Boston Healthcare System, Boston, MA, United States; Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, MA, United States; Anthinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, United States. 6. Translational Research Center for TBI and Stress Disorders (TRACTS) and Geriatric Research, Educational and Clinical Center (GRECC), VA Boston Healthcare System, Boston, MA, United States; Department of Psychiatry, Boston University School of Medicine, Boston, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States. 7. Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System, Little Rock, AK, United States.
Abstract
BACKGROUND: Evidence suggests that single nucleotide polymorphisms (SNPs) in genes involved in serotonergic signaling and stress response pathways moderate associations between PTSD and cortical thickness. This study examined a genetic regulator of these pathways, the PPM1F gene, which has also been implicated in mechanisms of stress responding and is differentially expressed in individuals with comorbid PTSD and depression compared to controls. METHODS: Drawing from a sample of 240 white non-Hispanic trauma-exposed veterans, we tested 18 SNPs spanning the PPM1F gene for association with PTSD and cortical thickness. RESULTS: Analyses revealed six PPM1F SNPs that moderated associations between PTSD symptom severity and cortical thickness of bilateral superior frontal and orbitofrontal regions as well as the right pars triangularis (all corrected p's < 0.05) such that greater PTSD severity was related to reduced cortical thickness as a function of genotype. A whole-cortex vertex-wise analysis using the most associated SNP (rs9610608) revealed this effect to be localized to a cluster in the right superior frontal gyrus (cluster-corrected p < 0.02). LIMITATIONS: Limitations of this study include the small sample size and that the sample was all-white, non-Hispanic predominately male veterans. CONCLUSIONS: These results extend prior work linking PPM1F to PTSD and suggest that variants in this gene may have bearing on the neural integrity of the prefrontal cortex (PFC).
BACKGROUND: Evidence suggests that single nucleotide polymorphisms (SNPs) in genes involved in serotonergic signaling and stress response pathways moderate associations between PTSD and cortical thickness. This study examined a genetic regulator of these pathways, the PPM1F gene, which has also been implicated in mechanisms of stress responding and is differentially expressed in individuals with comorbid PTSD and depression compared to controls. METHODS: Drawing from a sample of 240 white non-Hispanic trauma-exposed veterans, we tested 18 SNPs spanning the PPM1F gene for association with PTSD and cortical thickness. RESULTS: Analyses revealed six PPM1F SNPs that moderated associations between PTSD symptom severity and cortical thickness of bilateral superior frontal and orbitofrontal regions as well as the right pars triangularis (all corrected p's < 0.05) such that greater PTSD severity was related to reduced cortical thickness as a function of genotype. A whole-cortex vertex-wise analysis using the most associated SNP (rs9610608) revealed this effect to be localized to a cluster in the right superior frontal gyrus (cluster-corrected p < 0.02). LIMITATIONS: Limitations of this study include the small sample size and that the sample was all-white, non-Hispanic predominately male veterans. CONCLUSIONS: These results extend prior work linking PPM1F to PTSD and suggest that variants in this gene may have bearing on the neural integrity of the prefrontal cortex (PFC).
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