Researchers Identify Specific Genetic Vulnerabilities to PTSD among U.S. Veterans

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A genome-wide association study (GWAS) and bioinformatic analysis of more than 165,000 U.S. veterans confirms a genetic vulnerability to post-traumatic stress disorder (PTSD), specifically noting abnormalities in stress hormone response and/or functioning of specific brain regions, report scientists in a paper published July 29, 2019 in Nature Neuroscience.

GWAS are a relatively new scientific tool in which scientists rapidly scan markers across complete sets of DNA or genomes of many people, looking for genetic variations associated with a particular disease. The findings are used to develop better methods to detect, treat and prevent the disease.

In the new paper, a diverse team led by Murray B. Stein, MD, MPH, Distinguished Professor of Psychiatry and Family Medicine and Public Health at University of California San Diego School of Medicine and a psychiatrist at Veterans Affairs San Diego Healthcare System, and Joel Gelernter, MD, professor of psychiatry, genetics and neuroscience at Yale School of Medicine and VA Connecticut Healthcare System, sought to better parse the pathophysiology of PTSD — its underlying biological mechanisms — by analyzing genetic data from members of the Million Veteran Program, a national voluntary research effort funded by the Department of Veterans Affairs Office of Research & Development.

The scientists focused on finding genetic links relevant to “intrusive re-experiencing of trauma,” the most common symptom of PTSD, which is characterized by unintentional and unwanted recall, emotions and behaviors linked to past traumatic events, such as flashbacks.

The research sample consisted of 146,660 European American veterans and 19,983 African American veterans. In the European American group, the scientists found eight distinct genetic regions with strong associations between PTSD and how the brain responds to stress. It highlighted the role of one specific kind of brain cell: striatal medium spinal neurons, which are prevalent in a region of the brain responsible for, among other things, motivation, reward, reinforcement and aversion.   

“The genes implicated in this study point to this region of the brain, and these types of neurons, as potentially involved in PTSD vulnerability,” said Stein. “Because we know something about the regulation of these neurons, we can test hypotheses about drugs that might be useful for PTSD, such as drugs that influence dopamine or GABA, both of which are regulatory of these types of neurons.”

The researchers found no significant associations among the African American cohort, but Stein suggested the likely reason was the comparatively small size of the sample.

Stein said future research will be needed to replicate the findings, including postmortem PTSD analyses to confirm physiological effects on brain. The findings, he said, may also point to possible drug treatments to be explored.

Co-authors include: Joel Gelernter, Renato Polimanti, Robert Pietrzak, Daniel F. Levey, Ning Sun, Quan Chen and Hongyu Zhao, VA Connecticut Healthcare System and Yale University; Julien Bryois, Karolinska Institutet, Sweden; Qiongshi Lu, Yiming Hu, Boyang Li, Mihaela Aslan, John Concato, Kei-Hoi Cheung, Yuli Li, Nallakkandi Rajeevan and Frederick Sayward, Yale University; Krishnan Radhakrishnan, Yale University and University of Kentucky; Kelly Harrington, VA Boston Healthcare System and Boston University School of Medicine; Kelly Cho, Saiju Pyarajan and J. Michael Gaziano, VA Boston Healthcare System and Harvard Medical School; Patrick F. Sullivan, University of Kentucky and University of North Carolina; Rachel Quaden, Yunling Shi and Haley Hunter-Zinck, VA Boston Healthcare System.

Funding for this research came, in part, from the Million Veteran Program and VA Cooperative Studies Program study no. 575B.