New Research Shows Multiple Genes May Be Associated With PTSD

The search for the origins of posttraumatic stress disorder now extends beyond a triggering event into the affected individual’s genotype, which may eventually hold clues for more successful treatment, according to speakers at the 12th Annual Amygdala, Stress, and PTSD Conference. The conference was held at the Uniformed Services University of the Health Sciences in Bethesda, Md.

“It is clear that PTSD has a significant heritable component,” said Douglas Williamson, Ph.D., a professor of psychiatry and behavioral sciences at Duke University. “Estimates range from 26 percent to 38 percent of the risk.”

The Psychiatric Genetics Consortium has pooled data from hundreds of thousands of cases and controls in genomewide association studies to increase the ability to detect new loci of interest in PTSD. “What is needed now is evidence of the functional relevance of these newly identified loci,” he said.

Williamson is a principal investigator on the STRONG STAR Research Consortium, a pre- and post-deployment study that recruited 4,112 U.S. Army soldiers, collecting blood samples to look for genes that were up- or down-regulated following deployment. They identified 403 PTSD cases and 934 controls who had experienced or witnessed a traumatic event and endorsed having “intense fear, helplessness, or horror” as a result but had not reached case level.

Comparing the two groups, the researchers identified two novel genes: GRM7, associated with probable current PTSD symptoms, and OXSR1, associated with lifetime PTSD.

GRM7 serves as a presynaptic regulator of neurotransmission in the mammalian central nervous system and has been associated with major depression. GRM7 was downregulated in PTSD cases. Separate studies by Williamson’s Duke colleague Ahmad Hariri, Ph.D., based on more than 1,000 fMRI face-matching scans, found that coupling early traumatic stress exposure with the risk allele of GRM7 produced overactive responses to fearful faces and revealed higher levels of activity in both the left and right amygdalae following increased stress. Less is known about OXSR1, but it appears to regulate downstream kinases in response to environmental stress.

Other genes play a role as well. Postmortem human brain studies have found significant differences in gene expression in the subgenual prefrontal cortex (PFC) among patients with PTSD versus those with major depression or control subjects, reported Ronald Duman, Ph.D., a professor of psychiatry and neuroscience at Yale University School of Medicine. Output to the amygdala from the subgenual PFC is required to extinguish fear.

A study of 31 brains found that 169 genes were down-regulated and 107 upregulated in people diagnosed with PTSD, said Duman.

Most of these genes influenced cytokine and chemokine pathways, he said. “That suggests that psychological distress induces dysregulation of the immune system and that novel treatments or combinations of treatments should consider use of anti-inflammatories to keep that in check.”

Two genes in particular were tied to behaviors related to PTSD. SGK1 (serum glucocorticoid regulating kinase-1) was reduced in the subgenual PFC in brains from people with PTSD but not in those with major depressive disorder. Clinical research has shown a loss of glucocorticoids in PTSD patients, and studies of learned helplessness models in rats have noted a decreased expression of SGK1.

Decreased spine synapses are also reported in animals expressing the dominant negative allele, supporting the hypothesis that this leads to atrophy of those neurons, said Duman. Neuronal atrophy in the PFC, as seen in the retraction of dendrites and loss of spine synapses between neurons, is also caused by stress and may be involved in the inability to extinguish and possibly the inability to control functions of these glucocortical neurons, in the amygdala, nucleus accumbens, and many other brain regions that receive downstream projections, he said.

Blood levels of a second gene, the FK506 binding protein (FKBP5), are decreased in PTSD patients. Again, expression is greater in the subgenual PFC in PTSD patients, although not in patients with depression.

“Upregulation of SGK1 and FKBP5 may reduce fear and enhance extinction, so they also may serve as blood biomarkers for PTSD as well as for treatment response,” said Duman.

NPAS4, a brain-specific, activity-dependent transcription factor, is also upregulated in the subgenual PFC and may be a key hub gene for regulating other genes and transcription factors, he said. “NPAS4 inhibits excitatory synapses and excites inhibitory synapses to bring the circuit back into balance.”

As for treatment, ketamine has been observed to rapidly reduce symptoms in PTSD patients, said Duman. A single dose of ketamine significantly reverses the deficit in spine synapses in stressed animals and increases synaptic connections and the function of those neurons in the PFC.

“Ketamine may cause a big boost in synaptic connections that may improve the response to cognitive-behavioral therapy,” he said.

However, ketamine is also a drug of abuse and has serious side effects, so interest is switching to developing a ketamine-like drug that produces the same kind of rapid synaptic response but without unwanted side effects.

Duman would like to increase the number of his subjects to 110 and expand analysis to other parts of the PFC, the amygdala, and hippocampal subregions. One daunting factor that has already emerged is managing the vast quantity of information produced in these analyses, he said. More than 60 million pieces of data emerge from each sample, so bioinformatics is as important as biochemistry.

Williamson also noted the need to genotype larger populations of treated individuals to learn what genomes indicate which people respond best to which treatments over time. ■