title: Epigenetic and genetic variation at SKA2 predict suicidal behavior and post-traumatic stress disorder.
abstract: Traumatic stress results in hypothalamic pituitary adrenal (HPA) axis abnormalities and an increased risk to both suicidal behaviors and post-traumatic stress disorder (PTSD). Previous work out of our laboratory identified SKA2 DNA methylation associations with suicidal behavior in the blood and brain of multiple cohorts. Interaction of SKA2 with stress predicted suicidal behavior with ~80% accuracy. SKA2 is hypothesized to reduce the ability to suppress cortisol following stress, which is of potentially high relevance in traumatized populations. Our objective was to investigate the interaction of SKA2 and trauma exposure on HPA axis function, suicide attempt and PTSD. SKA2 DNA methylation at Illumina HM450 probe cg13989295 was assessed for association with suicidal behavior and PTSD metrics in the context of Child Trauma Questionnaire (CTQ) scores in 421 blood and 61 saliva samples from the Grady Trauma Project (GTP) cohort. Dexamethasone suppression test (DST) data were evaluated for a subset of 209 GTP subjects. SKA2 methylation interacted with CTQ scores to predict lifetime suicide attempt in saliva and blood with areas under the receiver operator characteristic curve (AUCs) of 0.76 and 0.73 (95% confidence interval (CI): 0.6-0.92, P = 0.003, and CI: 0.65-0.78, P < 0.0001) and to mediate the suppression of cortisol following DST (β = 0.5 ± 0.19, F = 1.51, degrees of freedom (df) = 12/167, P = 0.0096). Cumulatively, the data suggest that epigenetic variation at SKA2 mediates vulnerability to suicidal behaviors and PTSD through dysregulation of the HPA axis in response to stress.
authors: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors: Z
authors: Z
authors: Kaminsky
authors: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors: H C
authors: HC
authors: Wilcox
authors: Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors: W W
authors: WW
authors: Eaton
authors: Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: K
authors: K
authors: Van Eck
authors: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors: V
authors: V
authors: Kilaru
authors: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors: T
authors: T
authors: Jovanovic
authors: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors: T
authors: T
authors: Klengel
authors: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.|Mental Health Service Line, Department of Veterans Affairs Medical, Atlanta, GA, USA.
authors: B
authors: B
authors: Bradley
authors: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.|Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors: E B
authors: EB
authors: Binder
authors: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.|Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors: K J
authors: KJ
authors: Ressler
authors: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors: A K
authors: AK
authors: Smith
mesh_terms: D000328:Adult; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D057890:Epigenomics / Q000706:statistics & numerical data*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics*; D059020:Suicidal Ideation; D013405:Suicide / Q000706:statistics & numerical data*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C516428:SKA2 protein, human