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

Abstract

Methylation of the SKA2 (spindle and kinetochore-associated complex subunit 2) 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. About 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. Of all, 145 participants also had neuroimaging data available. Based on previous research, we examined DNA methylation at the cytosine–guanine locus cg13989295 as well as DNA methylation adjusted for genotype at the methylation-associated single nucleotide polymorphism (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.

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Acknowledgements

This research was supported in part by the NIMH grant R21MH102834 ‘Neuroimaging Genetics of PTSD’ and the Translational Research Center for TBI and Stress Disorders (TRACTS), a VA Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (B9254-C) and the Cooperative Studies Program, Department of Veterans Affairs. This research is the result of work supported with resources and the use of facilities at the Pharmacogenomics Analysis Laboratory, Research and Development Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas. This work was also supported by a Career Development Award to EJW from the United States Department of Veterans Affairs, Clinical Sciences Research and Development Program. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States Government.

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Correspondence to N Sadeh.

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Endnotes

(1) Three individuals with methylation levels >3 s.d. from the sample mean for each genotype were excluded from the study, resulting in a final N of 200. Supplemental analyses indicated that including these cases did not change the study findings.

(2) Current PTSD diagnosis was associated with decreased cortical thickness in the right frontal pole/SFG cluster (F1,143=4.75, P=0.031) and right OFC/IFG/rostral MFG cluster (F1,143=6.25, P=0.014), with a trend emerging for the left frontal cluster (F1,143=3.39, P=0.068). Cortical thickness in these clusters did not differ by MDD diagnostic status (F1,143<1.42, ps>0.23).

(3) DNA methylationadj was associated with a greater likelihood of current PTSD diagnosis (Wald χ2=4.35, OR=1.2, P=0.037), but not current MDD diagnosis. However, the relationship between DNA methylationadj and PTSD diagnosis were reduced to a trend-level when cell counts were entered in the model (Wald χ2=2.75, OR=1.1, P=0.097).

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Sadeh, N., Spielberg, J., Logue, M. et al. SKA2 methylation is associated with decreased prefrontal cortical thickness and greater PTSD severity among trauma-exposed veterans. Mol Psychiatry 21, 357–363 (2016). https://doi.org/10.1038/mp.2015.134

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