Abstract
BackgroundSuicide is the second leading cause of death among adolescents in the USA, and rates are rising. Methods to identify individuals at risk are essential for implementing prevention strategies, and the development of a biomarker can potentially improve prediction of suicidal behaviors. Prediction of our previously reported SKA2 biomarker for suicide and PTSD is substantially improved by questionnaires assessing perceived stress or anxiety and is therefore reliant on psychological assessment. However, such stress-related states may also leave a biosignature that could equally improve suicide prediction. In genome-wide DNA methylation data, we observed significant overlap between waking cortisol-associated and suicide-associated DNA methylation in blood and the brain, respectively.ResultsUsing a custom bioinformatic brain to blood discovery algorithm, we derived a DNA methylation biosignature that interacts with SKA2 methylation to improve the prediction of suicidal ideation in our existing suicide prediction model across both blood and saliva data sets. This biosignature was independently validated in the Grady Trauma Project cohort and interacted with HPA axis metrics in the same cohort. The biosignature showed a relationship with immune status by its correlation with myeloid-derived cell proportions in all data sets and with IL-6 measures in a prospective postpartum depression cohort. Three probes showed significant correlations with the biosignature: cg08469255 (DDR1), cg22029879 (ARHGEF10), and cg24437859 (SHP1), of which SHP1 methylation correlated with immune measures.ConclusionsWe conclude that this biosignature interacts with SKA2 methylation to improve suicide prediction and may represent a biological state of immune and HPA axis modulation that mediates suicidal behavior.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0279-1) contains supplementary material, which is available to authorized users.
Highlights
Suicide is the second leading cause of death among adolescents in the USA, and rates are rising
Overrepresentation of peripheral cortisol-associated loci among brain-associated suicide genes To address our first objective, we attempted to address the degree to which peripheral blood- or saliva-based DNA methylation profiles are indicative of epigenetic profiles in the brain related to suicidal behaviors
For Genetics of Recurrent Early-Onset Depression (GenRED) Offspring, we identified 20,146 and 22,865 probes that were nominally associated with the area under the curve (AUC) of waking weekday cortisol in blood and saliva samples, respectively (Additional files 1 and 2)
Summary
Suicide is the second leading cause of death among adolescents in the USA, and rates are rising. Methods to identify individuals at risk are essential for implementing prevention strategies, and the development of a biomarker can potentially improve prediction of suicidal behaviors. Prediction of our previously reported SKA2 biomarker for suicide and PTSD is substantially improved by questionnaires assessing perceived stress or anxiety and is reliant on psychological assessment. Given the rising rates of suicide in the USA, methods to identify individuals at risk for implementing prevention strategies are urgently needed [3]. Our laboratory identified a DNA methylation mark that is associated with suicide in a postmortem brain tissue cohort at a CpG (cg13989295) located within a single nucleotide polymorphism (SNP), rs7208505, in the spindle- and kinetochore-associated protein 2 (SKA2) where the reference allele of rs7208505 eliminates the CpG.
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