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A clearer picture of how post traumatic stress disorder (PTSD) and major depressive disorder (MDD) affect the brain has been provided by genomics, possibly pointing to new drug targets and biomarkers for these and related disorders. Researchers from McLean Hospital and colleagues used a multiomic database, single-nucleus RNA sequencing (snRNA-seq), genetics, and proteomics to find shared mechanisms underlying both conditions, including altered gene expression and exons in the medial prefrontal cortex. These results were published May 24 in Science.

“PTSD is a complex pathological condition. We had to extract information across multiple brain regions and molecular processes to capture the biological networks at play,” said first author Nikolaos P. Daskalakis, MD, PhD, director of the neurogenomics and translational bioinformatics laboratory at McLean Hospital.

The researchers also noted that a history of childhood trauma and suicide were strong drivers of molecular variations in both disorders. MDD disease signals were most associated with male-specific results, suggesting that sex differences may underlie disease risk. 

Stress-related disorders develop over time, stemming from epigenetic modifications caused by the interplay between genetic susceptibility and traumatic stress exposure. Previous studies have uncovered hormonal, immune, methylomic (epigenetics) and transcriptomic (RNA) factors mostly in peripheral samples contributing to these diseases. But limited access to postmortem brain tissues from diseased PTSD patients has restricted characterization of brain-based molecular changes at the appropriate scale.

“Our primary goals for this study were to interpret and integrate differential gene and protein expression, epigenetic alterations and pathway activity across our postmortem brain cohorts in PTSD, depression and neurotypical controls,” said senior author Kerry Ressler, MD, PhD, chief scientific officer and director of the division of depression and anxiety disorders and neurobiology of the Fear Laboratory at McLean Hospital. “We essentially combined circuit biology with powerful multi-omics tools to delve into the molecular pathology behind these disorders.”

The team analyzed multi-omic data from 231 PTSD, MDD, and neurotypical control subjects, along with 114 individuals from replication cohorts for differences in three brain regions—the medial prefrontal cortex, the hippocampal dentate gyrus, and the central nucleus of the amygdala. They also performed snRNA-seq of 118 PFC samples to study cell-type-specific patterns and evaluated blood-based proteins in more than 50,000 UK Biobank participants to isolate key biomarkers associated with stress-related disorders. Finally, the overlap of these key brain-based disease process genes was compared with genome-wide association studies (GWAS)-based risk genes to identify PTSD and MDD risk.

Top disease-associated genes and pathways across regions, omics, and/or traits implicated biological processes in both neuronal and non-neuronal cells. These included molecular regulators and transcription factors, and pathways involved in immune function, metabolism, mitochondria function and stress hormone signaling.

“Understanding why some people develop PTSD and depression and others don’t is a major challenge,” said investigator Charles B. Nemeroff, MD, PhD, chair of the department of psychiatry and behavioral sciences at the Dell Medical School of UT Austin. “We found that the brains of people with these disorders have molecular differences, especially in the prefrontal cortex. These changes seem to affect things like our immune system, how our nerves work, and even how our stress hormones behave.”

The genetic components of the work build on a study published last month by researchers including Ressler and Daskalakis in Nature Genetics, in which they identified 95 locations, or loci in the genome (including 80 new) associated with PTSD. This multi-omic analyses found 43 potential causal genes for the disorder.

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