Neuropsychiatric conditions such as post-traumatic stress disorder (PTSD) have a wide array of symptoms that can often make it challenging to narrow down genetic biomarkers that are essential for disease diagnosis and research. For instance, does extreme arousal, anger, or irritation experienced by some have the same genetic basis as the tendency to re-experience traumatic events, another symptom of the disorder? Well now, a new genome-wide association study (GWAS) from investigators at Yale and the University of California, San Diego (UCSD) hopes to provide answers to some of these questions.
Findings from the new study—published recently in Nature Genetics through an article titled, “Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program”—uncovered intriguing genetic similarities between PTSD and other mental health disorders such as anxiety, bipolar disorder, and schizophrenia. Interestingly, the new findings also suggest that existing drugs commonly used for other disorders might be modified to help treat individual symptoms of multiple disorders.
“The complexity is still there, but this study helped us chip away at it,” said co-senior senior study investigator Joel Gelernter, PhD, a professor of genetics and neurobiology at Yale.
In the current study, the researchers analyzed the complete genomes of more than 250,000 participants in the Million Veteran Program, a national research program of the U.S. Veterans Administration that studies how genes, lifestyle, and military experiences affect the health and illness of military veterans. Among those participants were approximately 36,000 diagnosed with PTSD.
“We conducted genome-wide association analyses of over 250,000 participants of European (EUR) and African (AFR) ancestry from the Million Veteran Program using electronic health record-validated PTSD diagnosis and quantitative symptom phenotypes,” the authors wrote. “Applying genome-wide multiple testing correction, we identified three significant loci in European case-control analyses and 15 loci in quantitative symptom analyses. Genomic structural equation modeling indicated tight coherence of a PTSD symptom factor that shares genetic variance with a distinct internalizing (mood–anxiety–neuroticism) factor.”
Instead of looking just for gene variants shared by PTSD patients, the research team also searched for variants that have been linked to three kinds of clinical symptoms that are experienced, to varying degrees, by those diagnosed with the disorder. These symptom groups, or “subdomains,” include the re-experience of a traumatic event, hyperarousal, or acute anger and irritability, and the avoidance of people or subjects that might be related to past trauma.
While the researchers found underlying genetic commonalities among all three symptom groups, they also discovered specific variants linked to only one or two of the symptoms.
“We found a remarkably high degree of genetic relatedness between these three symptom subdomains. But we also wouldn’t expect them to be genetically identical, and they are not,” Gelernter explained. “We found biological support for different clinical presentations of PTSD.”
The new findings also showed that some of the variants found in subgroups of patient symptoms are also linked to other disorders such as major depression. The results suggest drugs used to treat other disorders might also help treat PTSD.
“Our research pointed to some medications that are currently marketed for other disease states and could be repurposed for PTSD,” said co-senior study investigator Murray Stein, PhD, a professor of psychiatry and public health at UCSD.
Intriguingly, some of the variants linked to all PTSD symptoms have been associated with other neuropsychiatric disorders. For instance, PTSD-associated variants of the gene MAD1L1, which helps regulate cell cycling, have also been linked to schizophrenia and bipolar disorder.
“These observations and the recent finding of GWS [genomewide-significant] association with anxiety suggest that MAD1L1 may be a general risk factor for psychopathology,” the authors concluded.
