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GWAS of Veterans Ties Four Genetic Loci to Risk of Suicidal Thoughts, Behaviors

NEW YORK — In a large-scale study of military veterans, researchers have uncovered a handful of genetic loci associated with an increased risk of having suicidal thoughts or behaviors.

The study combined a genome-wide association analysis with electronic health record data on 633,778 US veterans from the US Million Veteran Program, 121,211 of whom had had suicidal thoughts or behaviors, and found four genes that were strongly tied to having such experiences.

As the team, led by investigators at Duke University, noted in JAMA Psychiatry on Wednesday, these four genes — ESR1, DRD2, TRAF3, and DCC — have each previously been linked to other psychiatric conditions. However, none had been found in a previous study the researchers conducted that focused on suicide attempts, rather than having suicidal thoughts or behaviors.

By better understanding the molecular basis of having suicidal thoughts or behaviors, the researchers hope to be able to better predict who might be at risk for suicide, which is the cause of more than 700,000 deaths a year in the US and has been increasing in rate, especially among military veterans. "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," co-first author Nathan Kimbrel, associate professor of psychiatry at Duke, added in a statement.

The MVP cohort included 121,118 individuals of African, 8,285 of Asian, 452,767 of European, and 51,608 of Hispanic ancestry, enabling the researchers to conduct both cross- and single-ancestry analyses. In their cross-ancestry analysis, they first identified more than 200 risk loci for having suicidal thoughts or behaviors, five of which they replicated using data from the International Suicide Genetics Consortium, a cohort of more than 549,000 individuals.

The four strongest of these signals could be traced to the ESR1, DRD2, TRAF3, and DCC genes, all of which have been implicated in other psychiatric conditions.

For instance, ESR1, which encodes an estrogen receptor, has been identified as a causal driver gene for post-traumatic stress disorder and depression — which are themselves risk factors for having suicidal thoughts or behaviors among veterans — and as a likely causal variant for anxiety. DRD2, meanwhile, has been linked to other key risk factors like schizophrenia, mood disorders, and engaging in risky behaviors, and TRAF3 has been tied to antisocial behavior, substance use, and attention-deficit/hyperactivity disorder. DCC, further, has been linked to multiple psychiatric disorders.

Gene-based tests uncovered two dozen additional cross-ancestry risk genes, which, the researchers added, represent an area for future study.

In ancestry-specific analyses, the researchers identified seven loci unique to the European-ancestry cohort and one locus each within the African ancestry and Hispanic ancestry cohorts. No ancestry-specific loci were found among the Asian-ancestry cohort. Four of these were also independently replicated: POM121L2 and METTL15/LINC02758 among European-ancestry individuals, PET112/GATB among African-ancestry individuals, and an intergenic locus on chromosome 4 among Hispanic-ancestry individuals.

Though these genes are potential candidate risk genes for having suicidal thoughts or behaviors, the researchers cautioned that more work needs to be done to determine how they may affect clinical care.

"While genes account for a small amount of risk relative to other factors, we need to better understand the biological pathways that underlie a person's risk for engaging in suicidal behavior," Kimbrel said, adding that "[t]he more we know, the better we can prevent these tragic deaths."

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