Study unveils genetic underpinnings of PTSD

BUSM/VA Boston Healthcare System investigators identify new gene linked to post-traumatic stress disorder

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BOSTON—A study published last month in the Nature journal MolecularPsychiatry by investigators at BostonUniversity School of Medicine (BUSM) and the Veterans Affairs (VA) BostonHealthcare System identifies a gene linked to post-traumatic stress disorder(PTSD), representing an important step toward identifying the geneticunderpinnings of the disorder.
While previous studies have examined the molecular geneticsof PTSD, results of those studies have been inconsistent and the heritabilityof PTSD remains largely unexplained. The BUSM-VA study, "A genome-wideassociation study of post-traumatic stress disorder identifies theretinoid-related orphan receptor alpha (RORA) gene as a significant risklocus," is the first genome-wide association study (GWAS) of PTSD.
The American Psychiatric Association (APA) formallyrecognized PTSD as an anxiety disorder in the early 1980s. The timing of thatrecognition was not coincidental, as it was first characterized in the periodfollowing the Vietnam War.
But PTSD isn't limited to combat veterans. The APA definesit as "a psychiatric disorder defined by profound disturbances in cognitive,emotional, behavioral and physiological functioning that occurs in response toa psychologically traumatic event." The APA further specifies that "thediagnosis applies to individuals who develop a constellation of symptoms afterexposure to an event involving perceived or threatened loss of life, seriousinjury or loss of physical integrity."
"Some other examples of causes of PTSD include rape andsexual assault, crime victimization and even motor vehicle accidents involvingdeath or serious injuries. The truth is, studies have shown that the majority,if not all people, will experience an event in their life that will meet thedefinition for a traumatic experience," says Dr. Mark W. Miller, an associateprofessor at BUSM and a clinical research psychologist in the National Centerfor PTSD at the VA Boston Healthcare System.
Miller, who served as the study's principal investigator,explains that VA centers often have affiliations with universities or researchcenters because this enables their investigators to apply for U.S. NationalInstitutes of Health grants and other federal agency funding.
"I have a longstanding interest in looking at howpersonality relates to PTSD, specifically in looking at how individualdifferences and personality traits might predict or influence the manifestationof post-traumatic reactions," Miller says. "One of the challenges of doing thissort of work is that we have this 'chicken-and-egg' problem with personalityand PTSD. It's difficult to demonstrate what came first."
With PTSD, the ideal research design would involve "studyinga large sample of people before they have been exposed to any traumatic event.Then they somehow get exposed to the exact same trauma, and you follow uplongitudinally," says Miller.
Obviously, that approach isn't possible, but there are manycurrent military studies that observe soldiers prior to deployment to warzones, with comparative follow-up afterwards.
"Even then, they will differ a lot in terms of learninghistory and experience with trauma," says Miller. "I started studying geneticsbecause it is a way to avoid some of the conceptual and methodologicalchallenges in looking at the relationship between personality and PTSD.  Studying DNA appealed to me because itis traditionally conceptualized as a static blueprint for one's different individualcharacteristics. It's also an attractive, state-of-the-art, fundable area ofresearch to delve into."
The BUSM-VA article reports the first positive results of aGWAS of PTSD and suggests that variations in the RORA gene are linked to thedevelopment of PTSD. RORA has been known to play a role in circadian rhythms,regulation of sex hormone systems and neuroprotection. It has been implicatedin other GWAS studies of other psychological conditions like bipolar disorder,attention deficit disorder and autism, and Miller's study indicates that it mayalso be involved in the development of PTSD.
Miller and his colleagues examined trauma-exposed, Caucasianveterans and their intimate partners (295 cases and 196 controls). Severalsingle-nucleotide polymorphisms (SNPs) yielded evidence of association. OneSNP, located in RORA, reached genome-wide significance. Nominally significantassociations were also observed for other RORA SNPs in two African-Americanreplication samples—one from the veteran cohort (43 cases and 41 controls) andanother independent cohort (100 cases and 421 controls). However, only theassociated SNP from the veteran African-American replication sample survivedgene-level multiple-testing correction.
These results suggest that individuals with the RORA riskvariant are more likely to develop PTSD following trauma exposure and point toa new avenue for research on how the brain responds to trauma, says Miller.
"Our study is an interesting development underscoring therole of RORA in behavior, psychological disorders and PTSD, and this areacertainly deserves more attention," Miller says. "We are in the process ofapplying for additional grants so we can take the next step, which is to studythe intersection of RORA variation, structural brain parameters and PTSD."
The study was supported by the National Institute of MentalHealth and a grant from the U.S. Department of Veterans Affairs. Miller'sco-authors were Drs. Mark Logue, a research assistant professor at BUSM and theBoston University School of Public Health, and Clinton Baldwin, a professor atBUSM.

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