Researchers studying genetic data from 200,000 people have found that the heritability of post-traumatic stress disorder is similar to that of depression and other forms of mental illness.
Large study reveals PTSD has a strong genetic component like other psychiatric disorders
Post-traumatic stress disorder (PTSD) is one of the most common psychiatric disorders, affecting some eight million adults at some point in their lifetime in the United States alone. Despite this, it is not clear why only some people who experience a traumatic event go on to develop PTSD. Some researchers have suggested that the disorder is only a social construct, but previous studies have hinted that genetics has some role. Now a new study confirms a clear biological basis for PTSD.
In the largest and most diverse genetic study of PTSD to date, scientists from more than 130 institutions participating in the Psychiatric Genomics Consortium (PGC) have found that PTSD has as strong of a genetic component as other psychiatric disorders. Genetics, they write in Nature Communications, accounts for between five and 20 percent of the variability in PTSD risk following a traumatic event.
The study team also reports that, like other psychiatric disorders and many other human traits, PTSD is highly polygenic, meaning that it is associated with thousands of genetic variants throughout the genome, each making small contributions to the disorder. Six genomic regions ("loci") harbor variants that were strongly associated with disease risk, providing some clues about the biological pathways involved in PTSD.
Based on these findings, we can say with certainty that there is just as much of a genetic component to PTSD risk as major depression and other mental illnesses.
"Based on these findings, we can say with certainty that there is just as much of a genetic component to PTSD risk as major depression and other mental illnesses," said Karestan Koenen, an associate member of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, a professor of psychiatric epidemiology in the Harvard T.H. Chan School of Public Health, and senior author on the study. “Our limited ability to study the living human brain and uncover the biological roots of PTSD has contributed to the lack of treatments and the stigma around this debilitating condition. Genetics helps us make new discoveries, find opportunities for new therapies, and counter that stigma.”
"Our long-term goal is to develop tools that might help clinicians predict who is at greatest risk for PTSD and personalize their treatment approaches," said study corresponding author Caroline Nievergelt, an associate professor in the department of psychiatry at the University of California San Diego (UCSD), and associate director of neuroscience in the Center of Excellence for Stress and Mental Health at the San Diego Veterans Administration. "We can’t always protect people from trauma. But we can treat them in the best ways possible, at the best time."
PTSD is polygenic
To conduct the study, Koenen, Nievergelt, and their colleagues worked with the PGC's PTSD working group and Cohen Veterans Bioscience, a non-profit organization dedicated to accelerating PTSD and traumatic brain injury research. Together, they built a 12-country network of more than 200 researchers, assembling data and DNA samples from more than 60 groups of people with PTSD and control subjects, including participants in the UK Biobank. At more than 200,000 people, the combined cohort is ten times larger than the first PGC PTSD study, published in 2017, and includes both civilians and members of the military. The cohort is also the most ancestrally diverse for any psychiatric genetics study to date, with more than 23,000 people with PTSD of European ancestry and more than 4,000 of African ancestry.
"Our study is distinguished by the fact that it’s international and is highly diverse," Nievergelt noted. "There’s greater representation here than in most studies to date."
Supported by lead analyst Adam Maihofer at UCSD, the team used the data to conduct a genome-wide association study (GWAS), using statistical tests to measure the effect of common genetic variants at millions of points across the genome on someone's likelihood of developing PTSD.
The analysis uncovered DNA variants at six loci that were strongly associated with PTSD risk. Three of the six loci were specific to certain ancestral backgrounds — two European and one African — and three were only detected in men. The six loci hint that inflammatory and immune mechanisms may be involved in the disorder, which is consistent with findings from previous studies.
A substantial number of variants across the whole genome had some level of association with PTSD, showing the disorder to be highly polygenic. The researchers conclude that PTSD's heritability — the level of influence genetics has on the variability of PTSD risk in the population — is between five and 20 percent, with some variability by sex. These findings held true across different ancestral groups.
Plots of genetic findings from the PTSD study. Data points above the red lines indicate regions of the genome significantly associated with PTSD. (Credit: Nievergelt CM et al. Nature Communications, 2019.)
As many behavioral traits and psychiatric disorders have some shared genetic basis, the team also looked for genetic correlations between PTSD and 235 other disorders, behaviors, and physical traits. They found significant overlap with 21, including depression, schizophrenia, neuroticism, insomnia, asthma, and coronary artery disease.
"Similar to other mental disorders, the genetic contribution to PTSD correlates with that for many other traits," Koenen said. "Further research is needed to determine what this means — whether some of the same genes that influence risk for PTSD also influence risk for other diseases like, for example, depression."
In a first step towards finding ways to tell who will develop PTSD, the research team used the UK Biobank data to develop a polygenic score that could possibly predict one's risk of developing PTSD following a traumatic event. Polygenic scores tally the effects of millions of genetic variations into a measure that can predict an individual's likelihood of exhibiting a certain trait or having a disorder.
The team tested their scores on data from men in the UK Biobank dataset, finding that those with the highest scores had 0.4-fold higher odds of developing PTSD than those with the lowest.
Similarly, when applied to data from the Million Veterans Program (which is studying how genes, lifestyle, and military exposures affect health and illness), people with the highest scores had a significant increase in the risk of re-experiencing traumatic memories — a key PTSD symptom.
The study authors emphasized that polygenic scores are not ready for clinical use. Even larger studies with more diverse datasets are needed to improve the accuracy of PTSD prediction and confirm the genetic findings.
"If you look across psychiatric genetics, it's taken even larger sample sizes than what we have here to make robust genetic discoveries," Koenen said. "This is a good start, but this needs to be a truly inclusive, large-scale, team-based scientific effort if we're going to continue to lay the groundwork for more effective interventions and treatments for the millions of people struggling with PTSD."
Support for this study was provided by the Cohen Veterans Bioscience, the National Institute of Mental Health, the US Army Medical Research and Materiel Command, the Stanley Center for Psychiatric Research at the Broad Institute, and other sources.
Nievergelt CM, et al. International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci. Nature Communications. Online October 8, 2019. DOI: 10.1038/s41467-019-12576-w.
Duncan LE, et al. Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability. Molecular Psychiatry. Online April 25, 2017. DOI: 10.1038/mp.2017.77.