Genomic variation in the SKA2 gene has recently been identified as a promising 
suicide biomarker. In light of its role in glucocorticoid receptor 
transactivation, we investigated whether SKA2 DNA methylation influences 
cortisol stress reactivity and is involved in the development of post-traumatic 
stress disorder (PTSD). Increased SKA2 methylation was significantly associated 
with lower cortisol stress reactivity in 85 healthy individuals exposed to the 
Trier Social Stress Test (B=-173.40, t=-2.324, p-value=0.023). Next, we observed 
that longitudinal decreases in SKA2 methylation after deployment were associated 
with the emergence of post-deployment PTSD symptoms in a Dutch military cohort 
(N=93; B=-0.054, t=-3.706, p-value=3.66 × 10(-4)). In contrast, exposure to 
traumatic stress during deployment by itself resulted in longitudinal increases 
in SKA2 methylation (B=0.037, t=4.173, p-value=6.98 × 10(-5)). Using 
pre-deployment SKA2 methylation levels and childhood trauma exposure, we found 
that the previously published suicide prediction rule significantly predicted 
post-deployment PTSD symptoms (AUC=0.66, 95% CI: 0.53-0.79) with an optimal 
sensitivity of 0.81 and specificity of 0.91. Permutation analysis using random 
methylation loci supported these findings. Together, these data establish the 
importance of SKA2 for cortisol stress responsivity and the development of PTSD 
and provide further evidence that SKA2 is a promising biomarker for 
stress-related disorders including PTSD.