Four Genes Discovered To Increase Risk of Suicidal Thoughts and Actions

A genome-wide analysis has identified genes that commonly appear in veterans who have a documented history of suicidal thoughts or actions.

A comprehensive study involving military members, led by researchers at Duke University and the Durham VA, has uncovered four genes linked to an increased likelihood of suicidal thoughts and behaviors.

Although further research is required to determine if these genetic markers can lead to targeted treatments, the study’s findings provide a deeper understanding of how inherited risk factors contribute to the development of suicidal thoughts and actions.

“It’s important to note that these genes do not predestine anyone to problems, but it’s also important to understand that there could be heightened risks, particularly when combined with life events,” said Nathan Kimbrel, Ph.D., associate professor in the Department of Psychiatry & Behavioral Sciences at Duke and co-lead author of the study publishing online Dec. 14 in the journal JAMA Psychiatry.

Kimbrel and colleagues, including co-lead author Allison Ashley-Koch, professor in the Department of Medicine at Duke, conducted a large, diverse, genome-wide analysis using data from 633,778 U.S. military veterans. Of the participants, 71.4% were of European ancestry; 19.1% African ancestry; 8.1% Hispanic; 1.3% Asian. Study participants were primarily male, with 9% female.

Within that group of veterans, 121,211 cases of suicidal thoughts or actions were identified from medical records. Participants were classified as controls if they had no documented lifetime history of self-harm behaviors.

Through a genome-wide analysis of blood samples, the researchers identified numerous genes that were evident among participants with documented cases of suicidal thoughts or actions, regardless of their ancestral background. Four genes had the strongest links, and have been previously associated with psychiatric conditions:

• ESR1, an estrogen receptor, has been previously identified as a causal genetic driver gene of PTSDPost-traumatic stress disorder (PTSD) is a psychiatric disorder that develops in some people who have experienced or witnessed a shocking, scary, or dangerous event.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>PTSD and depression, which are risk factors for suicidal behaviors among veterans. Estrogen is also suspected as a cause of sex differences in depression rates, and loss of ESR1 has been found to produce effects on brain tissue in men.
• DRD2, a dopamine receptor, has been associated with suicide attempts, schizophrenia, mood disorders, ADHDAttention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by an ongoing pattern of excessive amounts of inattention, hyperactivity, carelessness, and impulsivity that are pervasive, impairing, and otherwise age-inappropriate.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>ADHD, risky behaviors, and alcohol use disorder.
• DCC, which is expressed in brain tissue across the lifespan, has been associated with multiple psychiatric conditions and is elevated in the brains of people who die by suicide.
• TRAF3 is associated with antisocial behavior, substance use, and ADHD. Lithium — a gold standard treatment for bipolar disorder shown to reduce suicide risk — modulates the expression of TRAF3 and several other inflammatory genes.

In addition to those genes, the researchers also identified nine additional ancestry-specific risk genes.

“While genes account for a small amount of risk relative to other factors, we need to better understand the biological pathways that underly a person’s risk for engaging in suicidal behavior,” Kimbrel said. “Suicide is the cause of over 700,000 deaths annually and is the fourth-leading cause of death among people ages 15 to 29 years old. The more we know, the better we can prevent these tragic deaths.”

Reference: “Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans” by Nathan A. Kimbrel, Ph.D., Allison E. Ashley-Koch, Ph.D., Xue J. Qin, Ph.D., Jennifer H. Lindquist, MS, Melanie E. Garrett, MS, Michelle F. Dennis, BA, Lauren P. Hair, MA, Jennifer E. Huffman, Ph.D., Daniel A. Jacobson, Ph.D., Ravi K. Madduri, Ph.D., Jodie A. Trafton, Ph.D., Hilary Coon, Ph.D., Anna R. Docherty, Ph.D., Niamh Mullins, Ph.D., Douglas M. Ruderfer, Ph.D., Philip D. Harvey, Ph.D., Benjamin H. McMahon, Ph.D., David W. Oslin, MD, Jean C. Beckham, Ph.D., Elizabeth R. Hauser, Ph.D., Michael A. Hauser, Ph.D., for the Million Veteran Program Suicide Exemplar Workgroup, the International Suicide Genetics Consortium, the Veterans Affairs Mid-Atlantic Mental Illness Research, Education, and Clinical Center Workgroup, and the Veterans Affairs Million Veteran Program, 14 December 2022, JAMA Psychiatry.
DOI: 10.1001/jamapsychiatry.2022.3896