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.

Figure 1

Sliding window analysis of lifetime suicide attempt prediction. Barplots of the area under the receiver operator characteristic curve (AUC) generated using the suicide prediction model (y axis) as a function of childhood trauma scores. For each group (x axis), individuals are included if they fall within a window of (a) ±30 points on the total Child Trauma Questionnaire (CTQ) scores, (b) ±5 points on the emotional abuse subscale, (c) ±5 points on the sexual abuse subscale and (d) ±5 points on the physical abuse subscale from the Grady Trauma Project (GTP) cohort. Differences in sliding window lengths (±30 versus ±5) allow for inclusion of similar sample numbers per group (mean sample size ~57 per window for all analyses). Vertical red bars represent the windows where 95% confidence intervals for the AUC do not encompass a null prediction of 0.5. Barplots of the mean suicide attempt (SA) minus non-SA score generated by the suicide prediction model (y axis) as a function of the middle position of sliding window encompassing all individuals within a window of (e) ±30 points on the total CTQ scores and those representing only ±5 points on the (f) emotional abuse, (g) sexual abuse and (h) physical abuse subscales (x axis) from the GTP cohort. All vertical red bars represent those windows where 95% confidence intervals for the AUC do not encompass a null prediction of 0.5.

Figure 2

Suicidal behavior prediction models incorporating trauma exposure. A three-dimensional depiction of the effect of the genotype-corrected SKA2 3'-untranslated repeat (UTR) DNA methylation (z axis) interaction with trauma status (x axis) on suicide attempt as simulated in the (a) Grady Trauma Project (GTP) and (b) Prevention Research Study (PRC) cohorts (y axis).

Figure 3

Receiver operator characteristic (ROC) curves of suicide attempt prediction in blood and saliva. ROC curves generated by the model generated in the Prevention Research Study (PRC) cohort and predicting suicide attempt in the GTP cohort in (a) blood and (b) saliva. The training set data from the PRC cohort was generated by a linear model of suicide attempt as a function of the interaction of SKA2 3'-UTR DNA methylation and genotype at rs7208505 with trauma scores, additively controlling for race, sex and age. Prediction in the GTP cohort input SKA2 3'-UTR DNA methylation adjusted for past substance abuse and rs7208505 genotype interacting with either total CTQ scores or anxiety (HAM-A) scores, whereas additively controlling for age and sex. CTQ, Child Trauma Questionnaire; GTP, Grady Trauma Project; UTR, untranslated repeat.