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Million Veteran Program GWAS Uncovers Genetic Loci Linked to PTSD

NEW YORK — Researchers have tied more than a dozen genetic loci to risk of post-traumatic stress disorder or symptoms related to PTSD. 

While between half and 85 percent of people in the US experience traumatic events, not everyone develops PTSD, suggesting other factors influence vulnerability to the disorder.

Using data from the Million Veteran Program — which started in 2011 with the aim of identifying genetic influences on disease and health — researchers from the Department of Veterans Affairs and elsewhere conducted genome-wide association studies to tease out genetic factors influencing PTSD risk. As they reported in Nature Genetics on Thursday, the researchers identified three significant loci linked to PTSD among individuals of European ancestry in their cohort and 15 loci linked to symptoms of PTSD, underscoring the role of genetics in disease risk. 

"There is a genetic basis [or] component to PTSD that can help us understand its underlying biology, and that understanding will lead us to discovering novel treatments," first author Murray Stein, a professor of psychiatry at the University of California, San Diego, and a staff psychiatrist at the VA San Diego Healthcare System, said in an email.

The researchers analyzed their MVP cohort of 48,221 cases and 217,223 controls in two ancestry-determined groups and conducted a combined meta-analysis. PTSD status of the veterans was determined using a previously validated algorithm that was applied to data from their electronic health records.

The European ancestry GWAS uncovered three genetic risk loci — including one near MAD1L1 — and the African ancestry GWAS uncovered two genetic risk loci with genome-wide significance. The combined meta-analysis identified two risk loci, both near ones uncovered in the European ancestry GWAS, but pointing to different lead SNPs.

Similarly, a meta-analysis of the European MVP data and data from Psychiatric Genomics Consortium (PGC)-PTSD GWAS noted four genetic loci, two of which were near loci identified in the European MVP GWAS, including MAD1L1.

The researchers also conducted GWAS of PTSD symptoms — which include re-experiencing avoidance, and hyperarousal — based on a 17-item self-report of symptoms completed by participants. Within the European ancestry group, the researchers identified 15 genetic loci associated with a total symptom severity score, dubbed PCL-Total, and generated a list of top SNPs linked to specific symptoms. MAD1L1 was linked not only to PCL-Total, but also to the individual phenotypes re-experiencing, avoidance and hyperarousal.

MAD1L1, the researchers noted, has been implicated in other psychiatric disorders such as schizophrenia and bipolar disorder, suggesting that it might represent a general risk factor for psychopathology.

In a transcriptome-wide analysis of PCL-Total, the researchers found that expression of CRHR1 is increased in a number of brain tissues implicated in PTSD. This suggested to them that drugs influencing CRHR1 could be therapeutic candidates for PTSD treatment. However, they noted that a small trial of a CRHR1 antagonist had disappointing results, though that trial only included women.

Their analysis additionally suggested other drug classes that could be repurposed as PTSD treatments, such as acetylcholine receptor antagonists or angiotensin receptor antagonists.

Stein noted that while some drug candidates could be more beneficial for patients with certain genotypes, it could also turn out that his team's approach to drug discovery "will point to treatments that are universally (or close) effective for PTSD."

He added that they plan to follow up as the MVP cohort grows, as well as to dig deeper into their data to tease out other possible drug candidates.