title: SKA2 Methylation is Involved in Cortisol Stress Reactivity and Predicts the Development of Post-Traumatic Stress Disorder (PTSD) After Military Deployment.
abstract: 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.
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Marco P
authors.identifier: http://orcid.org/0000-0001-6163-7484
authors.initials: MP
authors.lastname: Boks
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Bart P F
authors.initials: BP
authors.lastname: Rutten
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands.|Research Centre Military Mental Healthcare, Ministry of Defence, The Hague, The Netherlands.
authors.forename: Elbert
authors.initials: E
authors.lastname: Geuze
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Lotte C
authors.initials: LC
authors.lastname: Houtepen
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands.|Research Centre Military Mental Healthcare, Ministry of Defence, The Hague, The Netherlands.|Department of Psychiatry, Leiden University Medical Center, Utrecht, The Netherlands.|Arq Psychotrauma Expert Group, Diemen, The Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Vermetten
authors.affiliation: Department of Psychiatry and Behavioral Sciences, The Mood Disorders Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.|Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Kaminsky
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Christiaan H
authors.initials: CH
authors.lastname: Vinkers
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D008889:Military Personnel; D013313:Stress Disorders, Post-Traumatic / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D002868:Chromosomal Proteins, Non-Histone; C516428:SKA2 protein, human; D006854:Hydrocortisone