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Published Online: 31 October 2014

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., and Zachary A. Kaminsky, Ph.D.Authors Info & Affiliations

Publication: American Journal of Psychiatry

Volume 171, Number 12

https://doi.org/10.1176/appi.ajp.2014.14010008

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Abstract

Considerable research suggests that suicide involves effects of genes, the environment, and their interaction. Analysis of three independent data sets of post-mortem brains revealed signs of increased methylation in one particular gene, SKA2, a finding that was extended to peripheral blood samples from other cohorts of prospectively followed individuals.

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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Information & Authors

Information

Published In

American Journal of Psychiatry

Volume 171 • Number 12 • December 01, 2014

Pages: 1287 - 1296

PubMed: 25073599

History

Received: 2 January 2014

Revision received: 2 April 2014

Revision received: 7 May 2014

Accepted: 19 May 2014

Published ahead of print: 31 October 2014

Published online: 1 December 2014

Published in print: December 01, 2014

Authors

Affiliations

Jerry Guintivano, Ph.D.

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.

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Tori Brown

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Alison Newcomer, M.Sc.

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Marcus Jones

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Olivia Cox, B.Sc.

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Brion S. Maher, Ph.D.

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William W. Eaton, Ph.D.

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Jennifer L. Payne, M.D.

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Holly C. Wilcox, Ph.D.

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Zachary A. Kaminsky, Ph.D.

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Notes

Address correspondence to Dr. Kaminsky ([email protected]).

Funding Information

Drs. Wilcox and Kaminsky are listed as co-inventors on a patent to evaluate risk of suicidal behavior using genetic and epigenetic variation at the SKA2 locus. Dr. Payne received legal consulting fees from Pfizer, AstraZeneca, and Johnson and Johnson and research support from Corcept Therapeutics. The other authors report no financial relationships with commercial interests.Supported in part by NIMH grant MH-094771 to Dr. Kaminsky, the Johns Hopkins Center for Mental Health Initiatives, the Solomon R. and Rebecca D. Baker Foundation, and the James Wah Award for Mood Disorders; subjects were collected with funding from the American Foundation for Suicide Prevention to Dr. Wilcox, National Institute on Drug Abuse grant DA-09897 to Dr. Eaton, and NIMH grant MH-074799 to Dr. Payne; human subjects research for the GenRED offspring cohort, prospective cohort, and PRC cohort was conducted under IRB protocols 00015387, 00008149, and 000000354; and human tissue was obtained from the National Institute of Child Health and Human Development’s Brain and Tissue Bank for Developmental Disorders and the University of Maryland, Baltimore.

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Identification and Replication of a Combined Epigenetic and Genetic Biomarker Predicting Suicide and Suicidal Behaviors

Abstract