Understanding Suicide Biomarker SKA2: Discovery of a Suicide Biosignature to Augment SKA2 Suicide Prediction and Investigating SKA2 Regulatory Mechanisms
Embargo until
Date
2017-06-05
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Johns Hopkins University
Abstract
Suicide is the 2nd leading cause of death for ages 10-34 in the United States. Suicide rates have risen dramatically since 1999, with an estimated 25 attempts per single completed suicide, calling for increased efforts to improve prevention strategies. Suicide is a state that is associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The spindle and kinetochore associated complex 2 (SKA2) gene was recently discovered as a biomarker of suicide and HPA-axis dysregulation. Genetic and epigenetic variation at rs7208505, a single nucleotide polymorphism located in the 3’ untranslated region of SKA2, interacted with stress/anxiety metrics to predict suicidal behavior. Additionally, SKA2 was downregulated in the brains of suicide decedents. Little is known concerning the regulation and function of SKA2 in regards to HPA-axis dysregulation or suicide. The goal of this dissertation was to improve suicide prevention by enhancing our existing SKA2 suicide prediction model to better identify at-risk individuals, and to increase understanding of underlying suicide biology by investigating the regulation of SKA2.
We used a custom bioinformatics approach to derive a DNA methylation biosignature that both interacted with rs7208505 methylation in post mortem prefrontal cortex and predicted suicide attempt in peripheral blood samples. Replacing stress/anxiety metrics in the SKA2 suicide prediction model with this biosignature improved prediction of suicidal behaviors. Additionally, the biosignature showed associations with immune modulation and HPA-axis metrics, suggesting that it may represent a biological state that mediates suicidal behavior. To better understand SKA2 regulation in the context of suicide, we screened various pathway agonists for alterations of SKA2 expression. We observed SKA2 downregulation in response to both anoxia and low iron conditions. Knockdown experiments revealed that this regulation was not due to the canonical hypoxia-inducible factor (HIF) pathway.
Together, these studies offer an enhanced suicide prediction model and new understanding of underlying biology and molecular mechanisms. This improved suicide prediction model will allow for and enhances ability to identify at-risk individuals and implement interventions to prevent future suicide attempts. With further development, knowledge of SKA2 and other molecular signaling pathways that are involved in HPA-axis dysregulation will allow for development of treatments targeting these pathways.
Description
Keywords
Suicide, Biomarker, SKA2