Discovery and replication of a peripheral tissue DNA methylation biosignature to augment a suicide prediction model

Suicide is the second leading cause of death among adolescents in the USA, and rates are rising.

We 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.

Using 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. Conclusions: We 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.