Summary: A new study reveals shared and distinct molecular changes in the brains and blood of people with PTSD and MDD. Research reveals how these disorders affect various brain regions, cell types and genomic layers, highlighting key molecular pathways and potential biomarkers.
The results provide insight into the development of targeted treatments and real-time blood diagnostics. This comprehensive approach could lead to new therapies for stress-related disorders.
Highlights:
- Multi-omics analysis: The study examined 231 individuals, analyzing gene and protein expression, epigenetic changes and pathway activity in multiple regions of the brain and blood.
- Distinct and shared changes: PTSD and MDD exhibit both shared and distinct molecular changes, particularly affecting the medial prefrontal cortex and associated with childhood trauma and sex-specific differences.
- Potential biomarkers: Research supports the development of blood biomarkers for stress-related disorders, bridging the gap between brain pathology and accessible diagnostic tools.
Source: McLean Hospital
A comprehensive approach that examines the intersection of multiple biological processes is needed to elucidate the development of stress-related disorders.
In a new study, researchers at McLean Hospital, part of the Mass General Brigham Health System, working with colleagues at the University of Texas at Austin and the Lieber Institute for Brain Development, discovered molecular changes both shared and distinct across brain regions and genomic layers. , cell types and blood in people with post-traumatic stress disorder (PTSD) and major depressive disorder (MDD).
These results, published on May 24th In Science, could pave the way for new treatments and biomarkers.
“PTSD is a complex 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 hospital’s Neurogenomics and Translational Bioinformatics Laboratory. McLean and associate professor of psychiatry at Harvard Medical School.
Stress-related disorders develop over time, resulting from epigenetic modifications caused by the interaction between genetic susceptibility and exposure to traumatic stress.
Previous studies have discovered hormonal, immune, methylomic (epigenetic), and transcriptomic (RNA) factors, primarily in peripheral samples contributing to these diseases, but limited access to postmortem brain tissue from PTSD patients has limited the characterization of brain molecular changes at the appropriate level. ladder.
“Our primary goals of this study were to interpret and integrate differential gene and protein expression, epigenetic alterations, and pathway activity in our postmortem brain cohorts in PTSD, depression and neurotypical controls,” said lead author Kerry Ressler, MD, PhD, chief scientific officer. and director of the Division of Depression and Anxiety Disorders and the Neurobiology of Fear Laboratory at McLean Hospital, and professor of psychiatry at Harvard Medical School.
“We essentially combined circuit biology with powerful multi-omics tools to delve deeper into the molecular pathology driving these disorders.”
To do this, the team analyzed multi-omics data from 231 PTSD, MDD and neurotypical control subjects, as well as 114 individuals from replication cohorts to detect differences in three brain regions: the medial prefrontal cortex (mPFC), the hippocampal dentate gyrus (DG) and the center. nucleus of the amygdala (CeA).
They also performed mononuclear RNA sequencing (snRNA-seq) of 118 PFC samples to study cell type-specific patterns and assessed blood proteins in more than 50,000 UK Biobank participants to isolate the key biomarkers associated with stress-related disorders.
Finally, the overlap of these key brain disease process genes was compared with risk genes based on genome-wide association studies (GWAS) to identify the risk of PTSD and MDD.
Individuals with PTSD and MDD both shared altered gene expression and exons in the mPFC, but differed in the location of epigenetic changes. Further analysis revealed that histories of childhood trauma and suicide were strong drivers of molecular variations in both disorders.
The authors noted that MDD disease signals were more strongly associated with male-specific outcomes, suggesting that gender differences may underlie disease risk.
Top disease-associated genes and pathways across regions, omics, and/or traits involved biological processes in neuronal and non-neuronal cells. These included molecular regulators and transcription factors, as well as pathways involved in immune function, metabolism, mitochondrial function and stress hormone signaling.
“Understanding why some people develop PTSD and depression and others do not is a major challenge,” said researcher Charles B. Nemeroff, MD, PhD, chairman of the Department of Psychiatry and Behavioral Sciences at Dell Medical School. from UT Austin.
“We discovered that the brains of people with these disorders have molecular differences, particularly in the prefrontal cortex. These changes appear 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 Natural genetics, in which they identified 95 locations, or loci in the genome (including 80 new ones) associated with PTSD. Their multi-omics analyzes found 43 potential disease-causing genes.
Researchers have now been able to reveal only limited overlap between key genes and those implicated in GWAS studies, highlighting the gap in current understanding between disease risk and underlying disease processes. In contrast, they found greater correlations between brain multi-omics and blood markers.
“Our results support the development of brain-informed blood biomarkers for real-time profiling,” Daskalakis said.
Ressler added: “These biomarkers could help overcome current challenges in obtaining brain biopsies to advance new treatments. »
Limitations of the study include biases inherent in postmortem brain research, including population selection, clinical assessment, comorbidities, and end-of-life status. The authors also caution that they have not fully characterized all cell subtypes and states, and that future studies are needed to understand contrasting molecular signals in omics or brain regions.
The team plans to use this database as a basis for future analysis of how genetic factors interact with environmental variables to create downstream disease effects.
“Learning more about the molecular basis of these conditions, PTSD and MDD, in the brain paves the way for discoveries that will lead to more effective therapeutic and diagnostic tools.
“This work has been possible thanks to brain donations to the Lieber Institute Brain Repository from families whose loved ones have died from these diseases,” said Joel Kleinman, MD, PhD, associate director of clinical sciences at the Lieber Institute for Brain Repository. brain development.
“We hope our research will one day bring relief to people struggling with these disorders and their loved ones.” »
Paternity: Other authors of the study from Mass General Brigham at McLean Hospital include Artemis Iatrou, Chris Chatzinakos, Aarti Jajoo, Clara Snijders, Christopher P. DiPietro, Ioulia Tsatsani, Cameron D. Pernia, Marina Soliva-Estruch, Vincent L Holstein, Justina F. Lugenbühl. , Mohammad SE Sendi and Sabina Berretta.
Co-authors include Dennis Wylie, Chia-Yen Chen, Dhivya Arasappan, Rahul A. Bharadwaj, Leonardo Collado-Torres, Stefan Wuchty, Victor E. Alvarez, Eric B Dammer, Amy Deep-Soboslay, Duc M. Duong, Nick Eagles , Bertrand R. Huber, Louise Huuki, Mark W. Logue, Adam X. Maihofer, Mark W. Miller, Caroline M Nievergelt, Geo Pertea, Deanna Ross, Benjamin B. Sun, Ran Tao, James Tooke, Erika J. Wolf, Zane Zeier, Psychiatric Genomics Consortium PTSD Working Group, Frances A. Champagne, Thomas Hyde, Nicholas T. Seyfried, Joo Heon Shin, Daniel R. Weinberger, Charles B. Nemeroff, and Joel E. Kleinman.
Disclosures: Nikolaos P. Daskalakis is a member of the scientific advisory boards of BioVie Inc., Circular Genomics, Inc. and Feel Therapeutics, Inc.; Daniel R. Weinberger serves on the advisory boards of Pasithea Therapeutics and Sage Therapeutics for unrelated work; Duc M. Duong is co-founder of ARC Proteomics, and co-founder and paid consultant of Emtherapro Inc.; Chia-Yen Chen is an employee of Biogen Inc.; Mohammad S. E Sendi receives consulting fees for work unrelated to Niji Corp. Benjamin B. Sun is an employee and shareholder of Biogen Inc.; Kerry J. Ressler has received consulting income from Alkermes and sponsored research support from Brainsway and Takeda, and serves on the scientific advisory boards of Janssen, Verily, and Resilience Therapeutics for unrelated work.
Funding: This work was supported by grants from NIMH, Brain & Behavior Research Foundation, Stichting Universitas/Bontius Foundation, Dutch Research Council (NWO) fund, and McLean Hospital.
About this news on research in genetics, mental health and neuroscience
Author: Ryan Jaslow
Source: McLean Hospital
Contact: Ryan Jaslow – McLean Hospital
Picture: Image is credited to Neuroscience News
Original research: Closed access.
“Dissecting the systems biology of PTSD and MDD across brain regions, cell types, and blood” by Nikolaos P. Daskalakis et al. Science
Abstract
Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood
INTRODUCTION
Stress-related disorders result from the interaction between genetic susceptibility and exposure to stress, occurring throughout the lifespan. Gradually, these interactions lead to epigenetic modifications of the human genome, shaping gene and protein expression.
Previous post-mortem brain studies have…
News Source : neurosciencenews.com
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