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Identification and Replication of a Combined Epigenetic and Genetic Biomarker Predicting Suicide and Suicidal Behaviors
Jerry Guintivano, Ph.D.; Tori Brown; Alison Newcomer, M.Sc.; Marcus Jones; Olivia Cox, B.Sc.; Brion S. Maher, Ph.D.; William W. Eaton, Ph.D.; Jennifer L. Payne, M.D.; Holly C. Wilcox, Ph.D.; Zachary A. Kaminsky, Ph.D.
Am J Psychiatry 2014;:. doi:10.1176/appi.ajp.2014.14010008
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From the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, and the Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore.

Address correspondence to Dr. Kaminsky (zkamins1@jhmi.edu).

Copyright © 2014 by the American Psychiatric Association

Received January 02, 2014; Revised April 02, 2014; Revised May 07, 2014; Accepted May 19, 2014.

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Abstract

Objective  Reliable identification of individuals at high risk for suicide is a priority for suicide prevention. This study was conducted to identify genes exhibiting epigenetic variation associated with suicide and suicidal behaviors.

Method  Genome-wide DNA methylation profiling was employed separately on neuronal and glial nuclei in a discovery set of postmortem brains from the National Institute of Child Health and Human Development to identify associations with suicide. Pyrosequencing-based validation was conducted in prefrontal cortical tissue in cohorts from the Stanley Medical Research Institute and Harvard Brain Bank at McLean Hospital and peripheral blood from three living groups. Functional associations with gene expression, stress and anxiety, and salivary cortisol were assessed.

Results  The DNA methylation scan identified an additive epigenetic and genetic association with suicide at rs7208505 within the 3′ untranslated region of the SKA2 gene independently in the three brain cohorts. This finding was replicated with suicidal ideation in blood from three live cohorts. SKA2 gene expression was significantly lower in suicide decedents and was associated with genetic and epigenetic variation of rs7208505, possibly mediated by interaction with an intronic microRNA, miR-301a. Analysis of salivary cortisol measurements suggested that SKA2 epigenetic and genetic variation may modulate cortisol suppression, consistent with its implicated role in glucocorticoid receptor transactivation. SKA2 significantly interacted with anxiety and stress to explain about 80% of suicidal behavior and progression from suicidal ideation to suicide attempt.

Conclusions  These findings implicate SKA2 as a novel genetic and epigenetic target involved in the etiology of suicide and suicidal behaviors.

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