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PTSD GWAS Meta-Analysis Leads to Identification of Ancestry, Sex-Specific Risk Loci

NEW YORK – A team from the University of California at San Diego, the Veterans Affairs San Diego Healthcare System, Cohen Veterans Bioscience, and elsewhere has tracked down several genetic loci with genome-wide significant ties to post-traumatic stress disorder (PTSD), though genetic risk factors seem to vary by ancestry and biological sex.

"These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations," corresponding author Caroline Nievergelt, a psychiatry researcher affiliated with UCSD and VA San Diego, and her colleagues wrote.

As they reported online yesterday in Nature Communications, Nievergelt and her colleagues did a genome-wide association study meta-analysis that included almost 207,000 individuals with or without PTSD. The search led to two loci with genome-wide significant associations to PTSD in individuals of European ancestry and a third locus with significant ties to PTSD in individuals with African ancestry. Three more loci were linked to the condition in men — two in men of European ancestry and one in men of African ancestry.

When the team used common variants from the analyses to put together a proposed polygenic risk score (PRS) for PTSD, the PRS appeared to significantly predict a key PTSD symptom known as "re-experiencing" in data from the US Million Veteran Program — a dataset that was also used in replication analyses for the study. Even so, the authors cautioned that specific loci did not necessarily carry over from one ancestry or study cohort to the next.

"Our findings provide further evidence of the need to invest in research that includes diverse ancestral populations, to expand reference data, and to continue to develop methods to analyze data from such populations," the authors wrote. "Until such an investment is made, we are limited in our ability to understand biological mechanisms, predict genetic risk, and produce optimal treatments for non-European populations." 

Although PTSD is thought to have a significant heritability, the team explained, it has been difficult to find common variants with consistent ties to the condition. In July, a GWAS focused on participants in the US Million Veteran Program highlighted eight loci with apparent ties to re-experiencing symptoms of PTSD in European Americans, for example, but none of these sites was significantly associated with re-experiencing in African Americans.

"Advances in understanding the genomic architecture of PTSD are critical for understanding the pathophysiology of this debilitating syndrome," they wrote, "and to developing novel biologically based treatment approaches."

Using data collected for 60 prior analyses, the investigators involved in the Psychiatric Genomics Consortium (PGC) PTSD Group compared genotyping profiles in 32,428 individuals with PTSD and in more than 174,200 unaffected control individuals, including UK Biobank participants.

"It is apparent from previous PGC work on other mental disorders that sample size is paramount for GWAS to discern common genome-wide significant variants of small effect that are replicable," they explained.

The team verified the heritability of PTSD — putting it at roughly 5 percent to 20 percent — before searching for PTSD-associated variants across the full cohort and in subgroups of individuals with European, African, and Native-American ancestry.

The European subgroup was made up of 23,212 individuals with PTSD and 151,447 controls, for example, and revealed two significant PTSD risk loci on chromosome 6. For their analysis of individuals of African ancestry, the researchers had access to data for 4,363 cases and almost 11,000 controls, which led to one significantly associated locus on chromosome 13.

In their gene-based analyses, the researchers saw an over-representation of variants in or around genes involved in immunity, neural development or neurocognition, or dopamine regulation, including the Parkinson's disease-related gene PARK2, which was implicated in the analysis of European individuals.

The variants and genes with apparent ties to PTSD overlapped to some extent with those implicated in other psychiatric conditions such as major depressive disorder, schizophrenia, or neuroticism, the researchers reported, though at least some of the sites seemed to be specifically associated with PTSD.

"These findings underscore the role and importance of better understanding the biological mechanisms and genetic risks associated with PTSD to help drive breakthroughs in prevention and treatment," co-author Magali Haas, president and CEO Cohen Veterans Bioscience, said in a statement.