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Post-Traumatic Stress Disorder GWAS in Million Veteran Program Participants Identifies Risk Loci

NEW YORK – A team led by investigators at the VA Connecticut Healthcare System; Yale University; the VA San Diego Healthcare System; and the University of California, San Diego has identified a handful of genetic loci linked to post-traumatic stress disorder risk in European American individuals.

Members of the team — which included representatives from the US Million Veteran Program (MVP) and the Department of Veteran Affairs Cooperative Studies Program — performed a genome-wide association study on 146,660 European American and 19,983 African American participants in MVP, searching for variants associated with the quantitative phenotype of interest: scores for the core PTSD symptom of reexperiencing traumatic events through nightmares or flashbacks.

"[U]sing the severity of the core PTSD phenotype — reexperiencing symptoms — for GWAS obviates the reliance on a categorical phenotype such as PTSD as defined according to the DSM or the International Classification of Diseases," corresponding authors Joel Gelernter, a researcher affiliated with Yale and the VA Connecticut Healthcare System, Yale, and Murray Stein, of UCSD and the VA San Diego Healthcare System, and their colleagues wrote.

Because PTSD diagnostic guidelines have changed over time, they explained, those criteria "have been proven to identify individuals with varying levels of symptom severity."

Based on genotypes obtained from Affymetrix Axiom custom arrays in these participants, the team narrowed in on eight parts of the genome that were associated with PTSD-related reexperiencing in the European Americans. None of the loci showed ties to PTSD reexperiencing in the African American participants.

In addition to validating the European American risk loci with data from the UK Biobank project, the researchers performed follow-up analyses based on genes, expression quantitative trait loci, tissue enrichment, or cell-type enrichment, demonstrating that the risk variants found in the European Americans fell in and around CRHR1 and other genes related to corticosteroid and steroid hormone pathways. They also saw enrichment for genes previously implicated in schizophrenia or other psychiatric conditions.

"Our results confirm prior biological knowledge regarding relationships with steroid response, and suggest new biological relationships that have implications for treatment response and precision medicine," the authors wrote.

Their findings, appearing online today in Nature Neuroscience, highlighted additional overlap between genes related to PTSD reexperiencing and genes identified in previous human or mouse studies that are expressed in striatal medium spiny neurons and in the brain cortex, hypothalamus, and other regions.

Genetic factors appear to contribute to PTSD, the team explained, and small studies published previously have hinted at some of the loci and genes that might be involved in the condition, which poses a particular concern for individuals who have served in the military.

"While PTSD can be attributable to a range of traumatic events," the authors wrote, "the nature and intensity of traumatic events experienced by some military personnel result in particularly high prevalence rates among US military veterans." 

Along with the genetic clues to PTSD that they uncovered in the European Americans, the authors suggested that findings from the analyses "demonstrate the immediate utility of the MVP samples for disorders prevalent in US veterans."

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