SKA2 methylation is associated with decreased prefrontal cortical thickness and greater PTSD severity among trauma-exposed veterans

Abstract

Methylation of the SKA2 gene has recently been identified as a promising biomarker of suicide risk. Based on this finding, we examined associations between SKA2 methylation, cortical thickness, and psychiatric phenotypes linked to suicide in trauma-exposed veterans. 200 trauma-exposed white non-Hispanic veterans of the recent conflicts in Iraq and Afghanistan (91% male) underwent clinical assessment and had blood drawn for genotyping and methylation analysis. 145 participants also had neuroimaging data available. Based on previous research, we examined DNA methylation at the CpG locus cg13989295 as well as DNA methylation adjusted for genotype at the methylation-associated SNP (rs7208505) in relationship to whole-brain cortical thickness, posttraumatic stress disorder symptoms (PTSD), and depression symptoms. Whole-brain vertex-wise analyses identified three clusters in prefrontal cortex that were associated with genotype-adjusted SKA2 DNA methylation (methylationadj). Specifically, DNA methylationadj was associated with bilateral reductions of cortical thickness in frontal pole and superior frontal gyrus, and similar effects were found in the right orbitofrontal cortex and right inferior frontal gyrus. PTSD symptom severity was positively correlated with SKA2 DNA methylationadj and negatively correlated with cortical thickness in these regions. Mediation analyses showed a significant indirect effect of PTSD on cortical thickness via SKA2 methylation status. Results suggest that DNA methylationadj of SKA2 in blood indexes stress-related psychiatric phenotypes and neurobiology, pointing to its potential value as a biomarker of stress exposure and susceptibility.

Contributions of polygenic risk for obesity to PTSD-related metabolic syndrome and cortical thickness

“…The genome-wide genotyping and cleaning of SNP data has been described in detail elsewhere (Sadeh et al, 2016) and will only be briefly described here. DNA was extracted from whole-blood samples, hybridized to Illumina HumanOmni2.5–8 microarrays, and scanned with an Illumina iScan System (Illumina, San Diego, CA) according to manufacturer’s protocol.…”

New translational perspectives for blood-based biomarkers of PTSD: From glucocorticoid to immune mediators of stress susceptibility

“…These differences have been proven functional at the gene expression or downstream neuroendocrinology levels in assays using primarily peripheral tissue (Daskalakis and Yehuda, 2014b), but it is expected that they have body-wide effects, as GR operates as a transcription factor across the body (Daskalakis et al, 2014). Functional genetic and epigenetic differences have been described also for genes encoding GR-chaperone proteins such as FK506-binding protein 5 (FKBP5), a GR-binding inhibitor, and spindle and kinetochore-associated protein 2 (SKA2), which is involved in GR-translocation to the nucleus (Binder et al, 2008; Boks et al, 2016; Kaminsky et al, 2015; Klengel et al, 2013; Sadeh et al, 2016). Interestingly, some of the observed traumatic stress- and/or PTSD-induced epigenetic effects could be intergenerationally transmitted (Daskalakis and Yehuda, 2014b; Perroud et al, 2014; Yehuda et al, 2015b; Yehuda et al, 2014a).…”

Neuroimaging genetic approaches to Posttraumatic Stress Disorder

“…In this way it facilitates negative feedback inhibition of the HPA axis, and is protective against the toxic effects of chronic HPA axis activity (Rice et al, 2008). The SKA2 SNP rs7208505 is associated with suicidal behavior (Guintivano et al, 2014), and recent evidence suggests it is also associated with brain structure differences in PTSD (Sadeh et al, 2015). The rs7208505 risk allele (C) can have varied methylation status, but the nonrisk allele (T) cannot be methylated (Guintivano et al, 2014).…”

“…The rs7208505 risk allele (C) can have varied methylation status, but the nonrisk allele (T) cannot be methylated (Guintivano et al, 2014). Because of this, Sadeh et al (2015) controlled for SKA2 SNP rs7208505 genotype so they could look at the relationship between this gene’s methylation status and PTSD. Participants were white, predominately male military veterans with Criterion A trauma.…”

“…Frontopolar cortex, SFG, and OFC are involved in diverse cognitive functions, for example, complex decision-making, attention, prospective thinking, introspection, and reward/punishment-related processing (e.g., Christoff & Gabrieli, 2000; Kringelbach & Rolls, 2004; Okuda et al, 2003). Differences in frontopolar cortex, SFG, and OFC structure could point toward dysfunction in their processing, for example, emotional dysregulation, impulsivity, and difficulty picturing the future (Sadeh et al, 2015). A path analysis suggested that SKA2 methylation status mediated the relationship between PTSD and cortical thickness in frontopolar cortex, SFG, and OFC.…”