Clues to complexity

NEW HAVEN, Conn. & SAN DIEGO—A study published in the journal Nature Genetics offers clues about the genetic causes of post-traumatic stress disorder (PTSD), genetic similarities between PTSD and other mental health disorders, and modifications of drugs used for other disorders (anxiety, bipolar disorder, and schizophrenia) that might be used for PTSD.

Researchers at Yale and the University of California, San Diego (UCSD) studied the whole genomes of more than 250,000 participants, including 36,000 people diagnosed with PTSD, in the Million Veteran Program. This national research program of the US. Veterans Administration seeks to learn how genes, lifestyle, and military exposures affect health and illness among veterans. Since launching in 2011, more than 825,000 veteran partners have joined this program on genetics and health.  

The study sought both gene variants common to PTSD patients, as well as variants that are associated with three kinds of clinical symptoms that are undergone by people who are diagnosed with the disorder. These groups are the re-experience of a disturbing event, hyperarousal or keen anger and irritability, and the evading of people or topics that could be related to previous trauma. Although there were underlying genetic commonalities in all three groups, there were also specific deviations attached to only one or two of the indicators.

According to the article, “The aims of these analyses are to provide: (1) a large, uniformly phenotyped from genome-wide association studies (GWAS) of PTSD in military veterans; (2) thorough exploration of subphenotypes; (3) replication of key associations in other datasets; (4) demonstration of the architecture of genetic association with other health-related phenotypes; (5) investigation of brain regions implicated; and (6) extension to possible drug targets. These aims were all accomplished with the overarching goal of deepening biological understanding to advance precision medicine for PTSD.”

The program used ancestry and diagnostic parameters supplied by the Million Veteran Program using electronic health record-validated PTSD diagnosis and quantitative symptom phenotypes. The researchers sought to “validate the biological coherence of the PTSD syndrome, inform its relationship to comorbid anxiety and depressive disorders and provide new considerations for treatment.”

The researchers explained that PTSD is “a serious mental disorder that can occur after exposure to extreme, life-threatening stress.” While 50 to 85 percent of Americans experience traumatic events during the course of a lifetime, most of them do not develop PTSD. Lifetime PTSD prevalence occurs in about 7 percent of the population, which suggests “differential resilience to stress and vulnerability to the disorder.” The researchers claim that there is a substantial heritable basis for PTSD risk, and evidence from GWAS demonstrates that “PTSD, like other mental disorders, is highly polygenic.” 

There is a wide variance in PTSD symptoms among people, and the current Diagnostic and Statistical Manual of Mental Disorders-5 definition allows for as many as “163,120 unique conformations for assembly of the disorder.” Because this phenotypic heterogeneity may make it difficult to detect genetic risk factors, other phenotypes or subphenotypes, such as re-experiencing (also known as intrusion) symptoms, that may reflect more biologically homogeneous entities have been studied.

Using genome-wide multiple testing correction, the researchers identified three significant loci in European case-control analyses and 15 loci in quantitative symptom analyses. They applied genomic structural equation modeling, which indicated tight coherence of a PTSD symptom factor that shares genetic variance with a distinct internalizing (mood–anxiety–neuroticism) factor. 

According to the paper, “Partitioned heritability indicated enrichment in several cortical and subcortical regions, and imputed genetically regulated gene expression in these regions was used to identify potential drug repositioning candidates. These results validate the biological coherence of the PTSD syndrome, inform its relationship to comorbid anxiety and depressive disorders and provide new considerations for treatment.”

While the researchers discovered a high degree of genetic relatedness among the three symptom subdomains, they determined that they are not genetically identical. They discovered biological support for different clinical presentations of PTSD. The team also determined that some the variants found in subgroups of patient symptoms are related to other disorders such as major depression, suggesting that drugs utilized to treat other disorders might be helpful in treating PTSD.

Co-senior author Murray Stein, Distinguished Professor of Psychiatry and Public Health at UCSD, said, “Our research pointed to some medications that are currently marketed for other disease states and could be repurposed for PTSD.”