Summary: People with PTSD tend to have higher expression of the SNRNP35 gene in their brains, and lower ZNF140 gene expression in their blood.
Source: McLean Hospital
Results from a new study suggest that whether certain genes are expressed — turned on or off– may play a role in susceptibility to post-traumatic stress disorder (PTSD). The study, which was conducted by an international team led by investigators at McLean Hospital and appears in the journal Cell Reports, may provide insights for PTSD prevention and treatment.
In the face of repeated, prolonged, or severe trauma, some individuals seem to be more susceptible to PTSD while others are resilient. Identifying which individuals may be susceptible to PTSD–and why–can help researchers develop effective interventions.
To investigate, scientists used genetic data from 195,684 individuals (29,539 with PTSD and 166,145 without), collected by the Psychiatric Genomics Consortium–PTSD Group (PGC-PTSD), to predict the expression patterns of genes in the brain and other tissues based on machine learning models. The team found two genes that were genetically predicted to be expressed at different levels in individuals with PTSD compared with those without PTSD.
Individuals with PTSD tended to have lower expression of a gene called SNRNP35 in the brain and higher expression of a gene called ZNF140 in the blood.
The researchers noted that SNRNP35 expression seems to be important in a region of the brain involved with managing stress. They also found that giving mice a high dose of a stress hormone decreases the expression of the SNRNP35 gene in the brain.
Regarding the ZNF140 gene, the protein coded by the gene is known to affect the expression of genes in immune cells circulating in the blood. Therefore, higher expression of ZNF140 may influence the body’s immune response to increase susceptibility to PTSD.
“Our study provides a road map for follow-up studies to link PTSD risk with vulnerable populations and to develop and validate biological tests and ‘druggable targets’ for prevention and treatment,” said lead author Nikolaos P. Daskalakis, MD, PhD, director of Neurogenomics and Translational Bioinformatics Laboratory at McLean Hospital.
The researchers noted that additional studies are also needed to uncover the detailed mechanisms behind different genes’ effects on PTSD susceptibility and resilience.
“Identifying the genetic influences of PTSD could help us understand how the body responds to traumatic experiences and may point to new interventions to help affected patients,” said senior author Kerry J. Ressler, MD, PhD, chief scientific officer and chief of McLean Hospital’s Center of Excellence in Depression and Anxiety Disorders.
Funding: Dr. Daskalakis was funded by a 2015 and a 2018 NARSAD Young Investigator grant from BBRF, a Jonathan Edward Brooking mental health research fellowship from McLean Hospital, and an appointed KL2 award from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences KL2TR002542, UL1TR002541). Dr. Ressler and PGC-PTSD were funded by Cohen Veterans Bioscience, the National Institute of Mental Health (NIMH) /U.S. Army Medical Research and Materiel Command grant R01MH106595, and One Mind Institute.
Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts
To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.