SKA2 methylation is associated with decreased prefrontal cortical thickness and greater PTSD severity among trauma-exposed veterans.
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 (methylation(adj)). Specifically, DNA methylation(adj) 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 methylation(adj) 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 methylation(adj) of SKA2 in blood indexes stress-related psychiatric phenotypes and neurobiology, pointing to its potential value as a biomarker of stress exposure and susceptibility.
National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA.|Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
N
N
Sadeh
Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.|Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, MA, USA.
J M
JM
Spielberg
Research Service, VA Boston Healthcare System, Boston, MA, USA.|Department of Biomedical Genetics, Boston University School of Medicine, Boston, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
M W
MW
Logue
National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA.|Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
E J
EJ
Wolf
Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
A K
AK
Smith
National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA.
J
J
Lusk
National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA.|Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.|Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, MA, USA.
J P
JP
Hayes
National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA.
E
E
Sperbeck
Translational Research Center for TBI and Stress Disorders and Geriatric Research, Educational and Clinical Center, VA Boston Healthcare System, Boston, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
W P
WP
Milberg
Translational Research Center for TBI and Stress Disorders and Geriatric Research, Educational and Clinical Center, VA Boston Healthcare System, Boston, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
R E
RE
McGlinchey
Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, MA, USA.|Department of Radiology, Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
D H
DH
Salat
Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
W C
WC
Carter
Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
A
A
Stone
Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
S A
SA
Schichman
Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA, USA.
D E
DE
Humphries
National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA.|Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
M W
MW
Miller
D000328:Adult; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D003863:Depression / Q000209:etiology; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D054542:Iraq War, 2003-2011; D016014:Linear Models; D008297:Male; D059906:Neuroimaging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017397:Prefrontal Cortex / Q000473:pathology*; D011569:Psychiatric Status Rating Scales; D013313:Stress Disorders, Post-Traumatic / Q000150:complications / Q000235:genetics* / Q000517:prevention & control*; D014728:Veterans; D055815:Young Adult
D002868:Chromosomal Proteins, Non-Histone; C516428:SKA2 protein, human