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.