Large epigenome-wide association study identifies multiple novel differentially methylated CpG sites associated with suicidal thoughts and behaviors in veterans.
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2023-01
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Abstract
Introduction
The U.S. suicide mortality rate has steadily increased during the past two decades, particularly among military veterans; however, the epigenetic basis of suicidal thoughts and behaviors (STB) remains largely unknown.Methods
To address this issue, we conducted an epigenome-wide association study of DNA methylation (DNAm) of peripheral blood samples obtained from 2,712 U.S. military veterans.Results
Three DNAm probes were significantly associated with suicide attempts, surpassing the multiple testing threshold (FDR q-value <0.05), including cg13301722 on chromosome 7, which lies between the genes SLC4A2 and CDK5; cg04724646 in PDE3A; and cg04999352 in RARRES3. cg13301722 was also found to be differentially methylated in the cerebral cortex of suicide decedents in a publicly-available dataset (p = 0.03). Trait enrichment analysis revealed that the CpG sites most strongly associated with STB in the present sample were also associated with smoking, alcohol consumption, maternal smoking, and maternal alcohol consumption, whereas pathway enrichment analysis revealed significant associations with circadian rhythm, adherens junction, insulin secretion, and RAP-1 signaling, each of which was recently associated with suicide attempts in a large, independent genome-wide association study of suicide attempts of veterans.Discussion
Taken together, the present findings suggest that SLC4A2, CDK5, PDE3A, and RARRES3 may play a role in STB. CDK5, a member of the cyclin-dependent kinase family that is highly expressed in the brain and essential for learning and memory, appears to be a particularly promising candidate worthy of future study; however, additional work is still needed to replicate these finding in independent samples.Type
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Kimbrel, Nathan A, Melanie E Garrett, Mariah K Evans, Clara Mellows, Michelle F Dennis, Lauren P Hair, Michael A Hauser, undefined VA Mid-Atlantic MIRECC Workgroup, et al. (2023). Large epigenome-wide association study identifies multiple novel differentially methylated CpG sites associated with suicidal thoughts and behaviors in veterans. Frontiers in psychiatry, 14. p. 1145375. 10.3389/fpsyt.2023.1145375 Retrieved from https://hdl.handle.net/10161/30070.
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Scholars@Duke

Nathan Andrew Kimbrel
My primary areas of interest include the etiology, assessment, and treatment of PTSD, depression, suicide, and non-suicidal self-injury. I primarily work with veterans, firefighters, and emergency medical personnel due to their high levels of occupational exposure to traumatic stress. I also have long-standing interests in genetics, epigenetics, GxE research, personality, smoking, comorbidity, and statistical modeling procedures, such as CFA, SEM, and mixture modeling.

Michael Arthur Hauser
Dr. Hauser has a strong interest in ocular genetics. Genomic studies at the Center for Human Genetics have identified multiple linkage peaks and susceptibility genes in primary open angle glaucoma (POAG) and age related macular degeneration (AMD). Dr. Hauser has recently accepted a 20% appointment at the Singapore Eye Research INstitute and the Duke/National University of Singapore. In collaboration with multiple collaborators in Singapore, and Dr. Rand Allingham at the Duke Eye Center, Dr. Hauser is currently conducting a genome wide association study for glaucoma in individuals of African ancestry. These investigations include large datasets collected in Ghana, Nigeria, and South Africa.
Dr. Hauser is also involved in collaborative investigations into the genetics of post-tramatic stress disorder in US veterans from Iraq and Afghanistan. Major collaborators include Dr. Allison Ashley Koch, Dr. Jean Beckham, Dr. Christine Marx and the MIRECC Collaborative group at the Durham Veteran's Administration. We have published a genome wide association study, as well as numerous investigations into candidate genes. Epigenomic DNA methylation analysis and gene expression analysis of 3500 individuals is currently ongoing.

Allison Elizabeth Ashley-Koch
My work focuses on the dissection of human traits using multi-omic technologies (genetics, epigenetics, metabolomics and proteomics). I am investigating the basis of several neurological and psychiatric conditions such as neural tube defects and post-traumatic stress disorder. I also study modifiers of sickle cell disease.

Jean Crowell Beckham
Interest in assessment and treatment of trauma, particularly as occurs for both women and men during military service; focus in treatment outcome of differential and collective contribution for psychopharmacological and behavioral interventions in PTSD populations; long term physical health effects of chronic posttraumatic stress disorder.
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