Invisible Wounds

What stress does to the soul

A Gene for PTSD?

Researchers have found a gene that can increase or decrease the risk of PTSD.

Researchers say they’ve found a gene that appears to increase or decrease the risk of post-traumatic stress disorder among combat vets.

If this study can be replicated, it could help answer the question of why one soldier experiencing trauma develops PTSD while another does not. That, in turn, could lead to ways to boost stress resilience.

“We’re really excited about this because it may help us open a new paradigm between PTSD and TBI,” says Dr. Mark Miller, a clinical and research psychologist with the VA's National Center for PTSD and an associate professor at Boston University School of Medicine. “People studying TBI-related impairments have found that TBI and PTSD are often highly correlated. What we’re thinking is that there may be some commonality that has a molecular basis to it. I’m kind of anticipating that next decade or so will show lot of advances in neuroprotective and neurodegenerative responses.”

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Miller and his team recently published an article in “Molecular Psychiatry” which explained the work they did in what’s believed to be the first genome-wide scan for genetic risk factors associated with PTSD. Their work followed up on studies of twins which showed that sensitivity to stress could be inherited, that it wasn’t totally a function of stress in the environment.

First came DNA samples from 496 military veterans and 233 of their spouses; 53.7 percent of the participants met the criteria for PTSD.  Then the researchers analyzed genetic data for association with PTSD using a microarray chip that contained probes for 2.5 million SNP (single-nucleotide polymorphisms) spread across the entire genome. 

“SNPs are rungs on the ladder of the DNA double helix called base pairs where there is known variation across humans,” Miller told me. That allowed researchers to see if the stressed vets shared any common genetic difference.

It turned out that they did, and it wasn’t a gene that Miller and his team were familiar with. They found a statistically significant association with a variant of the retinoic acid orphan receptor A (RORA) gene, which was unfamiliar to them at the time.

“RORA has never been linked to PTSD before to our knowledge,” said Miller, the study’s lead investigator. “But when we read up on it, we found that it had previously been linked to other disorders such as attention-deficit hyperactivity disorder, bipolar disorder, autism and depression. In other words, it was a psychiatrically relevant gene.”

One of the major roles of RORA is protecting brain cells from the damaging effect of injury and disease and possibly traumatic brain injuries, Miller told me. He believes RORA produces a protein that helps protect neurons from neurotoxic effects of stress, including oxidative stress. An imbalance between oxidants and antioxidants in a cell, oxidative stress can be caused by physical damage or traumatic stress.

“Our hypothesis is that those who have the RORA risk marker may have a RORA gene that is less capable of mounting a neuroprotective reaction to stress, causing structural damage and functional changes to neurons that RORA should be protecting,” said Miller.

Again, this is a new study that hasn’t been replicated, but if future studies bear out its findings, researchers may be able to develop gene therapies or pharmaceutical ways to enhance the function of the RORA gene. And that may help stress-vulnerable people become more resilient.

Incidentally, the genome-wide association study is an extremely broad-based look at all associations, rather than a selective look at just some of the usual suspects — specifically the dopamine and the serotonin systems.    

“We looked at the serotonin transporter valve and didn’t see any strong association,” Miller told me. “However, there’s plenty of literature supporting its importance. The caveat goes back to the limitations of GWAS. We have to apply such a strict statistical threshold that many lesser associations had to fall by the wayside. The fact that we didn’t find it in this study doesn’t mean it doesn’t play a role in the general population or in a population substrata.”

Nearly a decade ago, Avshalom Caspi published a groundbreaking paper in Science magazine that charted the lives (from 3 to 26 years old) of more than 1,000 white New Zealanders in what became known as the Dunedin Multidisciplinary Health and Development Study.

He focused on serotonin, the neurotransmitter that carries electrical signals across a synapse from one neuron to another, then gets sucked up by the first neuron to be used all over again. He noticed that about 17 percent of his study group had what’s known as a short form of the serotonin re-uptake valve, 51 percent had some short and some long forms of this gene, and 31 percent only had the long form (which apparently is more effective in sucking the serotonin back up).

All of his subjects experienced some form of trauma, but those with the long form of the serotonin re-uptake gene handled it better. Among the participants suffering four or more traumatic events, 33 percent with the short form became depressed as adults, compared with only 17 percent who had the long form.

This is another study that hasn’t been replicated, but that seems very promising. And Miller says he isn’t about to rule it out yet.

Eric Newhouse is a Pulitzer Prize-winning journalist and the author of Alcohol: Cradle to Grave and Faces of Combat: PTSD and TBI.

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