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Huge study explores genetics of PTSD in more than 165,000 US veterans

Dr. Michael Kennedy (left), a family medicine provider at Landstuhl Regional Medical Center, discusses the importance of proactive health readiness with Army Maj. Oscar Ochoa. With a focus of preventive prostate screening, healthy eating and physical fitness, Kennedy emphasized the importance of men to stay engaged in their health care and not to wait until the last minute to be seen by a primary care provider. (Stacy Sanning/US Army)

A new genetic study uses information from an unprecedented number of U.S. veterans to probe a particularly vexing question: Why does post-traumatic stress disorder affect some, but not others?

It is a particularly urgent question given that suicide rates are higher among veterans suffering from PTSD, which is estimated to affect between 11% and 20% of those who served in the military.

Recently published in the journal Nature Science by collaborating investigators at the University of California, San Diego and Yale University, the study is the first PTSD analysis to draw upon genetic information collected by the Million Veteran Program. Created by the U.S. Department of Veterans Affairs, the voluntary initiative seeks to create a medical database large enough that researchers can see patterns of genetic variation capable of providing indispensable road maps for the future treatment of many diseases.

Though the program does not yet have its full sampling of 1 million records available, there is already enough data in place to allow the research team to study more than 165,000 veterans. Using sophisticated computer modeling techniques, they were able to compare the genomes of those who experienced a key symptom of post-traumatic stress to those who did not.

Common genetic differences were observed at eight different DNA locations among veterans who reported “re-experiencing” a PTSD symptom associated with nightmares and flashbacks that are sometimes triggered by events similar to those that were present when trauma first occurred.

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Differences at three different chromosome locations were deemed to be most statistically significant and are thought to potentially affect the body’s hormone response to stress and, perhaps, to the function or structure of certain types of neurons in the brain.

Though mutations in these genes have previously been suspected to have something to do with PTSD susceptibility, science is increasingly finding it necessary to compare the genetic fingerprints of many, many real people in order to tease out which changes, among many possibilities, drive complex disorders such as PTSD.

Dr. Murray B. Stein, a UC San Diego psychiatry and family medicine professor who led the study with Dr. Joel Gelernter, a professor of genetics and neuroscience at Yale, was quick to note that this type of association study offers suggestions rather than clear answers. But correlating genetic information on such a large scale, he said, provides the kind of signal in the noise that can help guide deeper investigations in the future.

There are some suspicions, for example, that DNA differences more common in those who reported re-experiencing may affect the development or function of medium spiny neurons that are present in parts of the brain responsible for motivation, reward, reinforcement and aversion.

However, the presence of genetic changes alone is far from the whole story. A complex microbiological interplay decides which genes actually get expressed, and that dance is also affected by environmental factors. So, simply having a genetic difference itself is, researchers say, not likely to in-and-of-itself make a person more susceptible to PTSD.

Epigenetics, the study of which genes within a person’s DNA actually get expressed and how that translation occurs, are necessary to truly understand how genetic differences may influence real people.

In terms of those medium spiny neurons, Stein said, the association study provides hints that could provide the starting point for deeper epigenetic studies that could determine how, and in which specific circumstances, genetic code differences deliver heightened PTSD susceptibility.

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“Those genes could code for the way neurons are connected to their neighbors or it could code for ways that neurons are regulated by neurotransmitters. It could be any and all of various possibilities,” Stein said.

Though significantly more work would be needed, being able to see these genetic differences across large populations, Stein said, provides something of a road map, giving a notion of where to look for what might be driving a disorder. If those initial hints can be confirmed and more deeply explained, then a potential avenue for drug development can arrive.

“If you can understand, for example, how neurons are affected, it makes us look to see whether it’s possible that medications could influence and maybe benefit those neurons,” Stein said.

After reading the paper, Mark Miller, a clinical research psychologist with the VA Boston Health Care System and the VA’s National Center for PTSD, said it is heartening to see the era of big data arriving from the Million Veteran Program which has been more than a decade in the making.

“This is a demonstration of what the VA is capable of doing in terms of leveraging the Million Veteran Program for new scientific discoveries,” Miller said.

As to the study’s particular findings, Miller said he is most excited to see a strong correlation around a gene known as CRHR1. Scientists have long suspected that changes in this gene, which regulates a glandular grouping in the body called the hypothalamic-pituitary-adrenal axis, has something significant to do with PTSD susceptibility. Among many other critical functions, this grouping of the brain’s hypothalamus and the pituitary and adrenal glands regulates how the body processes stress.

The study’s ability to detect CRHR1 changes among those who reported re-experiencing previous traumas, he said, could help coalesce scientific consensus around how to study the axis in the future.

“CRHR1 is something that has been researched for decades using classical scientific investigation approaches,” Miller said. “Now we’re getting some convergence with this unbiased hypothesis-free approach to gene discovery.”

The study was split into two arms based on race with a cohort of nearly 20,000 African American veterans studied to see if they have a similar correlation of genetic differences as compared to the general veteran population. The study did not find such correlations, but Stein said that result is likely due to the much smaller number of available records. He said the study will be repeated as the Million Veteran Program collects more and more participants, which should eventually provide a large enough sample of African American veterans to see if similar changes are present.

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© 2019 The San Diego Union-Tribune

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