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.