Summary: A new study reveals shared and distinct
molecular changes in the brain and blood of individuals with PTSD and
MDD. The research uncovers how these disorders affect various brain
regions, cell types, and genomic layers, highlighting key molecular
pathways and potential biomarkers.
The
findings offer insights into the development of targeted treatments and
real-time blood-based diagnostics. This comprehensive approach could
lead to novel therapeutics for stress-related disorders.
Key Facts:
- Multi-Omics Analysis:
The study examined 231 individuals, analyzing gene and protein
expression, epigenetic changes, and pathway activity across multiple
brain regions and blood.
- Distinct and Shared Changes:
PTSD and MDD show both shared and distinct molecular changes,
particularly affecting the medial prefrontal cortex and associated with
childhood trauma and sex-specific differences.
- Potential Biomarkers:
The 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 necessary to elucidate the development of
stress-related disorders.
In
a new study, investigators from McLean Hospital, a member of the Mass
General Brigham healthcare system, working with colleagues at The
University of Texas at Austin and Lieber Institute for Brain
Development, uncovered both shared and distinct molecular changes across
brain regions, genomic layers, cell types, and blood in individuals
with posttraumatic stress disorder (PTSD) and major depressive disorder
(MDD).
These results, published May 24th in Science, could provide potential avenues for novel therapeutics and biomarkers.
“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, and an associate professor of psychiatry
at Harvard Medical School.
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 Division of Depression and Anxiety Disorders and
Neurobiology of Fear Laboratory at McLean Hospital, and a professor of
psychiatry at Harvard Medical School.
“We essentially combined circuit biology with powerful multiomics
tools to delve into the molecular pathology behind these disorders.”
For
this, the team analyzed multiomic 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 (mPFC), hippocampal dentate gyrus (DG) and central
nucleus of the amygdala (CeA).
They also performed single-nucleus
RNA sequencing (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.
PTSD and MDD individuals both shared altered gene expression
and exons in the mPFC, but differed in the localization of epigenetic
changes. Further analysis revealed that history 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 results, suggesting that sex differences may underlie
disease 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, M.D., PhD, chair of
the Department of Psychiatry and Behavioral Sciences at 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 built 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. Their multi-omic analyses found 43
potential causal genes for the disorder.
The
researchers now could reveal only limited overlap between the top genes
and those implicated in GWAS studies, underscoring the gap in current
understanding between disease risk and underlying disease processes. In
contrast, they discovered greater correlations between brain multi-omics
and blood markers.
“Our findings support the development of brain-informed blood biomarkers for real-time profiling,” said Daskalakis.
Ressler
added, “These biomarkers could help overcome current challenges in
obtaining brain biopsies for advancing new treatments.”
Limitations
of the study include the inherent biases in postmortem brain research,
including population selection, clinical assessment, comorbidities, and
end-of-life state. The authors also caution that they did not fully
characterize all cell-subtypes and cell states, and that future studies
are required to understand contrasting molecular signals across omics or
brain regions.
The team plans on using this database as
groundwork 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 was possible because of the brain donations to the Lieber
Institute Brain Repository from families whose loved ones died of these
conditions,” said Joel Kleinman, MD, PhD, associate director of Clinical
Sciences at the Lieber Institute for Brain Development.
“We hope our research will one day bring relief to individuals who struggle with these disorders and their loved ones.”
Authorship: Additional
Mass General Brigham authors of the study from 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 S. E
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, Μark 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, PTSD Working Group of Psychiatric
Genomics Consortium, 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 on the scientific advisory boards for BioVie Inc.,
Circular Genomics, Inc. and Feel Therapeutics, Inc.; Daniel R.
Weinberger is on the advisory boards of Pasithea Therapeutics and Sage
Therapeutics for unrelated work; Duc M. Duong is a cofounder of ARC
Proteomics, and cofounder and paid consultant of Emtherapro Inc.;
Chia-Yen Chen is an employee of Biogen Inc.; Mohammad S. E Sendi
receives consulting fees for unrelated work from Niji Corp, Benjamin B.
Sun is an employee and stockholder of Biogen Inc.; Kerry J. Ressler has
received consulting income from Alkermes and sponsored research support
from Brainsway and Takeda, and is on the scientific advisory boards for
Janssen, Verily, and Resilience Therapeutics for unrelated work.
Funding: This
work was supported by grants from NIMH, the Brain & Behavior
Research Foundation, Stichting Universitas / the Bontius Foundation,
Dutch Research Council (NWO) fund and McLean Hospital.
About this genetics, mental health, and neuroscience research news
Author: Ryan Jaslow
Source: McLean Hospital
Contact: Ryan Jaslow – McLean Hospital
Image: The image is credited to Neuroscience News
