NEW YORK – An international team has tracked down genetic contributors related to brain, neural, and other processes in post-traumatic stress disorder (PTSD), a life-altering condition found in almost 6 percent of trauma-exposed individuals, leading to mood changes, enhanced arousal, intrusive thoughts, and other symptoms.
The work "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," Caroline Nievergelt, a psychiatry researcher at UCSD, said in a statement.
In a study published in Nature Genetics on Thursday, Nievergelt and colleagues from the University of California, San Diego, Harvard, and other centers shared findings from a multi-ancestry genome-wide association study that brought together data for nearly 1.3 million individuals with or without PTSD who were enrolled through 88 prior studies. The participants included 137,136 PTSD-affected individuals of European ancestry, 11,560 cases with African ancestry, and 2,064 Native American ancestry cases.
"Importantly, previous GWAS are severely limited in generalizing their findings to non-European ancestries," the authors explained, noting that the inequality "is particularly troubling in the US given the disproportionately high burden of trauma and PTSD faced by populations of African, Native, and Latin American origin."
With their multi-ancestry meta-analysis approach, the team uncovered 80 new and 15 known loci with genome-wide significant ties to the condition.
An analysis specific to European ancestry participants led to 81 PTSD-linked loci, the researchers reported, while analyses focused on participants of African or Native American ancestry alone did not uncover genome-wide significant risk loci, potentially reflecting the smaller sample sizes in those populations.
By bringing in transcriptome-wide association study data, together with a Mendelian randomization analysis that hinged on brain gene expression insights from GTEx, the team focused in on 43 genes that appeared to have a causal role in PTSD.
The gene set was enriched for contributors to neurotransmitter, synaptic modulator, axon guidance, immune regulatory, endocrine, development, and transcription factor pathways, the researchers reported. Still other genes had been previously linked to stress, fear, threat response, or immune activity.
The potential role for brain and neural processes was backed up by the team's gene-set and gene-tissue analyses. On the gene enrichment side, for example, the data highlighted genes from a dozen functional groups, including central nervous system development, synaptic membrane, and nucleic acid binding pathways. PTSD-associated genes were expressed in a range of brain regions, tissue, and cell types, and in pituitary tissue.
"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," Kerry Ressler, a Psychiatric Genomic Consortium for PTSD co-leader, psychiatry researcher at Harvard, and CSO at McLean Hospital, said in a statement.
Ressler called the new data "an important first step in next-generation approaches to novel interventions for PTSD."
When the investigators considered polygenic risk scores (PRS) for PTSD, they found that the performance of PTSD PRSs declined significantly when applied to individuals from ancestry groups that were different from those used to establish a given PRS, consistent with the population-specific architecture described in the past.
"We know that trauma and PTSD disproportionately affects under-resourced populations globally, particularly African ancestry populations," senior author Karestan Koenen, a researcher with the Broad Institute and the Broad's Stanley Center for Psychiatric Research, said in a statement. "Our next steps will focus on addressing that inequity through partnerships with African scientists to make sure research in PTSD genetics benefits everyone equally."