A genetic study involving more than 1.2 million people has pinpointed 95 genetic loci that are associated with risk of developing post-traumatic stress disorder (PTSD), including 80 loci that had not been previously known. The study, by researchers with the PTSD working group within the Psychiatric Genomics Consortium (PGC-PTSD) together with Cohen Veterans Bioscience, is claimed to be the largest and most diverse of its kind, and also identified 43 genes that appear to play a role in causing PTSD. The findings both confirm previously discovered genetic underpinnings of PTSD and provide many novel targets for future investigation that could lead to new prevention and treatment strategies.

“This discovery firmly validates that heritability is a central feature of PTSD based on the largest PTSD genetics study conducted to date and reinforces there is a genetic component that contributes to the complexity of PTSD,” said Caroline Nievergelt, PhD, a professor in the department of psychiatry at the University of California, San Diego as well.

Co-first and corresponding author Nievergelt, together with co-first author Adam Maihofer, PhD, a genetic epidemiologist in Nievergelt’s lab, and colleagues reported on the study in Nature Genetics, in a paper titled “Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder,” in which they concluded, “These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.”

In PTSD, intrusive thoughts, changes in mood, and other symptoms after exposure to trauma can greatly impact a person’s quality of life. About six percent of people who experience trauma develop the disorder, but scientists don’t yet understand the neurobiology underlying PTSD. “… rates are higher in those with high levels and certain types of trauma exposure such as combat survivors and assault victims,” the authors explained. “PTSD is a chronic condition for many, posing a substantial quality-of-life and economic burden to individuals and society.”

Preclinical and human neuroimaging studies are helping to advance understanding of PTSD biology, but there are many questions remaining about the pathophysiology of the condition, and “… new targets are needed for prevention and treatment,” the authors continued.

Previous twin and genetic studies, including an investigation by the same team in 2017 and an expanded study in 2019, showed that PTSD has a genetic component, and that many genes contribute to the condition. But these analyses pointed to different genetic loci across datasets, and many studies struggled to distinguish loci that were specific to PTSD risk from those that were also linked to conditions such as depression and cardiovascular disease. Genetic datasets have also historically focused on people of European ancestry, even though there is a disproportionately high burden of trauma and PTSD among people of African, Native American, and Latin American ancestry in the United States and globally. “Without expansion to other ancestries, there is a risk that recent advances in PTSD genetics will result in the widening of research and treatment disparities,” the team stated.

For their newly reported study Nievergelt, Koenen, and other researchers from the PGC compiled data from 88 different genome-wide association studies (GWAS), which use genetic data from large groups of people to look for associations between regions of the genome and the chance of developing a condition or trait. In all, the dataset contained information about the risk of developing PTSD from more than 1.2 million individuals of European ancestry (including about 140,000 with PTSD), about 50,000 with African ancestry (including about 12,000 with PTSD), and about 7,000 with Native American ancestry (about 2,000 with PTSD). Importantly, their study included analyses of the X chromosome which, the team noted, “… comprises 5% of the human genome, and may be particularly important given sex differences in PTSD prevalence.”

Meta-analysis of the data revealed 95 genetic loci strongly associated with PTSD—“a fivefold increase over the most recent PTSD GWAS,” they noted—including 80 that had not been identified previously. “Compared to previous PTSD GWAS, we confirmed 14 of 24 loci and identified 80 new PTSD loci.”

The results identified 43 genes that appeared to play a role in causing PTSD, including genes impacting on neurons, neurotransmitters, ion channels, synapses, and the endocrine and immune systems. “These genes can broadly be classified as neurotransmitter and ion channel synaptic plasticity modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine and immune regulators (for example, ESR1, TRAF3 and TANK),” the authors further explained. “Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology.” They also found that PTSD shared many genetic features with depression, as well as several PTSD-specific loci.

Although previous studies found a higher prevalence of PTSD in females than males, the researchers did not find evidence for this in their data. Examining the X chromosome, they found five loci linked with PTSD. But they noted that these changes on the X chromosome would have similar effects in males and females.

To more deeply probe how PTSD genetics affect the brain, the team studied gene expression data and found that the cerebellum, the brain region that controls movement and balance, may be involved in the disorder in addition to region scientists have previously connected with PTSD, such as the cortex and amygdala. In particular, the research team found that interneurons, which connect motor and sensory neurons, were involved in PTSD risk. Future studies could help determine how key genes in these tissues and cells affect PTSD symptoms and behaviors.

“Future mechanistic research in preclinical models should examine whether targeting combinations of these genes, for example, via polygenic targeting, epigenetic or knockdown approaches, would have increased power in regulating stress, fear, cognitive dysfunction or other symptoms and behaviors seen in PTSD,” the investigators stated in their discussion. “Analyses in better-powered datasets may identify drug repositioning opportunities and could use the predicted effect of associated variants on gene expression to indicate whether drug candidates would be beneficial or contraindicated in people with PTSD.”

“For the first time, we are approaching a genetic architecture for PTSD, which both validates prior understanding of some of the critical biology underlying trauma-related disorders, while also pointing towards exciting and novel new targets and mechanisms,” said co-author Kerry Ressler, MD, PhD, a co-leader of the PGC-PTSD working group, chief scientific officer at McLean Hospital, and professor of psychiatry at Harvard Medical School. “These data are an important first step in next generation approaches to novel interventions for PTSD.”

In line with previous findings, Nievergelt, Koenen, and their colleagues also found that polygenic risk scores—a calculation of a person’s genetic chance of developing a certain condition based on millions of single-letter changes in their DNA—for PTSD risk are not readily translatable across populations. The researchers say this disparity highlights the importance of continuing to expand the depth and diversity of populations included in future studies of PTSD.

“We know that trauma and PTSD disproportionately affects under-resourced populations globally, particularly African ancestry populations,” said Koenen. “Our next steps will focus on addressing that inequity through partnerships with African scientists to make sure research in PTSD genetics benefits everyone equally.”

Karestan Koenen, PhD, senior author on the study, an institute member of the Broad Institute of MIT and Harvard, and an investigator with the Stanley Center for Psychiatric Research at Broad, said, “It’s exciting that we see the exponential increase in loci with increases in sample size we see for other disorders. This is a milestone for PTSD genetics.” Koenen leads the Stanley Center’s Biology of Trauma Initiative and the Global Neuropsychiatric Genomics Initiative, and is a professor of psychiatric epidemiology at the Harvard T. H. Chan School of Public Health.

The authors further commented, “While these results represent a milestone in PTSD genetics and point to exciting potential target genes, further investment into data collection from underrepresented populations of diverse ancestries is needed for the identification of additional risk variants and to generate equitable and more robust PRS.”

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