It’s been 20 years since the first human genome was sequenced and 10 years since the birth of psychiatric genomics. Like those who study chronic conditions such as cancer, researchers in the field of psychiatric genomics are dedicated to using genome-wide association studies (GWAS) to find candidate genes that, upon further study, will reveal the biology behind mental health disorders. The ultimate goal is to find genetic variants that can be used in risk assessment, therapeutic development, and treatment matching. The search is also on for reliable biomarkers that can be used in diagnostics and disease state monitoring.
By just about every measure, however, the efforts to personalize mental healthcare is lagging far behind efforts to personalize the treatment of cancer, diabetes, and other chronic diseases. Unlike with cancer and heart disease, “we are pretty much nowhere in terms of using genetics to predict a disorder,” says Karestan Koenen, Ph.D., a professor of psychiatric epidemiology at the Harvard T. H. Chan School of Public Health.
Genomics has also yet to markedly impact the way people with mental health disorders are treated, says Rachel Yehuda, a professor and vice chair of psychiatry, and professor of neuroscience at the Icahn School of Medicine at Mount Sinai. She is also the mental health director at the Bronx Veterans Affairs (VA) and is a pioneer in the field of biological psychiatry. Yehuda is the first to do gene expression studies in mental health patients (see sidebar, page 25). “Sitting here 15 years later, I don’t think we have realized the dream,” she says.
Building a foundation
Harvard’s Koenen says GWASes are still the best bet for building a solid foundation for precision mental health care of the future. “In terms of identifying genes and understanding the biology—and especially identifying potential new areas that you wouldn’t have just thought of based on what we know so far—GWAS are proving to be highly informative.”
Koenen leads the Global Neuropsychiatric Genomics Initiative of the Stanley Center for Psychiatric Research at Broad Institute of Harvard and MIT. Creating a solid foundation for personalized mental health care means ensuring that GWAS are inclusive. To that end, she and her colleagues are seeking to diversify the genetic sample collection outside of the U.S. and Northern Europe through the Neuropsychiatric Genetics of African Populations (NeuroGAP) and Neuropsychiatric Genetics in Mexican Populations (NeuroMex) programs.
NeuroGAP is in its third year, while NeuroMex is in its first. The programs enroll patients in psychiatric medical settings who have either a diagnosis of schizophrenia or bipolar disorder. The control groups are made up of patients from other medical settings.
These programs are important, Koenen says, because they ensure that the true range of genetic diversity of humans is represented. “This extra data can provide insights into biology that can then be used to benefit everyone,” she adds. The studies also address current health disparities in the U.S. populations descended from these regions. “If we don’t address this explicitly by being inclusive of all populations and peoples in our research, the science will only make the disparities worse.”
Genetic complexity
Getting a representative sample of the genetic diversity of human beings with respect to mental health is vital due to the complexity of mental health disorders. Case in point: researchers over the years have identified 270 markers as being associated with schizophrenia. In 2019, researchers are the Broad Institute narrowed that list down to 10 genes that are directly tied to the disease. Later that year, the Cross-Disorder Group of the Psychiatric Genomics Consortium led by Harvard’s Jordan Smoller, M.D. found that many distinct psychiatric diseases share a common genetic structure.
The group, which published their findings in the December 2019 issue of Cell, analyzed 232,964 cases and 494,162 controls from GWAS of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. The researchers identified more than 100 genetic variants that affect the risk for more than one mental health condition.
The genetic clues provided by studies like these are invaluable, Smoller says. “You get a window into the underlying biology. Individual genetic variants are not acting by themselves, but they’re likely to be parts of biological networks or pathways. Despite the complexity,” he adds, “we still think that genetics is going to point us in directions that could really change the way we think about therapeutics and develop new therapeutics, because each genetic finding is likely to implicate some biology.”
Sussing out PTSD markers
But determining the actual biology underlying mental health disorders often is not a straightforward endeavor. One likely reason is because it is much more difficult to sample brain tissue than that of organs involved in other chronic diseases. But Mount Sinai’s Yehuda has developed a novel way of looking for biomarkers of PTSD. “It is critical to develop new techniques that will capture the dynamic transcriptional response associated with stress-activated conditions relative to baseline conditions,” she and her colleagues wrote in a 2019 paper published in Translational Psychiatry.
In the study, the researchers exposed cultured blood cells taken from combat veterans with and without PTSD to dexamethasone, a synthetic glucocorticoid. The stress hormone cortisol is a glucocorticoid and the impaired function of glucocorticoid receptors is implicated in the progression of PTSD. The researchers found that the gene expression patterns of dexamethasone stimulated blood cells from combat veterans with and without PTSD were better at differentiating the two groups than gene expression patterns for blood cells at baseline. The finding suggests that this method might be useful to identify novel markers of altered glucocorticoid signaling and responsivity in PTSD, the authors wrote.
Currently, Yehuda’s Mount Sinai group is working with the New York Stem Cell Research Foundation on experiments in which they look at the overlap in gene expression patterns between the dexamethasone stimulated blood and hydrocortisone-exposed neurons induced from fibroblast cells of combat veterans with PTSD (see image). “And, to the extent that we find overlap in gene expression patterns, that tells us the genetic risk because these neurons are just like three-month-old embryonic cells. All the gene expression patterns that you see in blood that you don’t see in the neurons might just be about what happens just in blood and not in the brain,” Yehuda says.
Assessing mental health risk
While Harvard’s Koenen notes that predicting a mental health disorder from a person’s genome is not yet applicable in the clinic, mental health genomic testing company Genomind has marketed a pharmacogenomic (PGx) test since 2016 called Genecept Assay aimed at helping to guide treatments.
Now, the company believes the science is has progressed to be able to assess a person’s mental health-related predispositions, though Genomind does not claim to predict disease risk. This year, the company will press forward with its plans to launch its Mental Health Map ($599), which, according to Genomind’s website, allows people to understand how their genetic profile influences behavior, mood, stress response so that they can take actions to ensure mental wellbeing. The test uses 35 genetic variants to identify predispositions for what Genomind calls the Seven Genetic Mental Health Capabilities:
- Mood
- Social Behavior
- Focus & Memory
- Stress & Anxiety
- Eating Behavior
- Habits & Substance Abuse
- Sleep
Since it’s beta launch in the summer of 2020, Mental Health Map has been popular with patients who have had success with the PGx product. “Patients who are parents want to know what mental health challenges their children are likely to face,” says Genomind’s CEO Shawn O’Brien. “I know this product would have made me a better-prepared parent.”
O’Brien says he expected the test to be popular with physicians and patients. What he didn’t expect was for employers to start lining up to offer the test to their employees as part of their benefits packages. “They see it as preventative mental healthcare that could mean less suffering for their employees and more healthcare savings for them,” he adds.
Revolutionizing diagnostics
During her career, Mount Sinai’s Yehuda has worked with people who have experienced a variety of traumatic situations—from Holocaust victims to Vietnam veterans. Her clinical work eventually led her to do groundbreaking work in psychiatric genomics, including the first study of gene expression associated with PTSD in 9/11 first-responders. The 2009 study published in Biological Psychiatry showed that several genes involved in glucocorticoid signaling are differentially expressed among those with current PTSD.
Yehuda was granted a patent for the technology behind what could be the first test used to assess risk for PTSD—and in a few years—diagnose it. That’s the hope of the co-founders of TruGenomix, which has licensed the technology. The company’s TruGen-1 tests for gene expression levels for FKBP5, STAT5B and NFIA—genes that control cortisol levels. According to the company’s website: “When expression of these biomarkers differs, people experience a prolonged and more extreme stress response and the onset of PTSD symptoms.”
The company is currently in talks with the VA to collaborate on clinical trials that would first use their assay to determine risk for PTSD. Later, it hopes to use the test to diagnose disease and have embarked on a pathway to gain regulatory approval of a PTSD test in the future. Such a test would, at a minimum, be a vast improvement over diagnostic tools—survey questionnaires—currently used to diagnose the disease.
“We want to bring some objectivity to the diagnosis process and be able to identify PTSD much earlier. We believe that’s the value—cost savings to the system—and that’s also saving people potential pain that they would go through because they were undiagnosed,” says Charles Cathlin, TruGenomix CEO. A veteran himself, he wants to be able to tell PTSD sufferers who don’t believe they have a disease there is a biological basis to PTSD; that their body’s stress response has gone awry. “With a diagnostic, we can change the conversation. I think that that would be helpful for everyone,” he adds.
Despite the fact that her technology may lead to the first diagnostic test for a mental health disorder, Yehuda notes more progress should have been made by now in the identification of biomarkers. “If you’re on the right track and so much money is being thrown at the problem, and everybody’s doing this work in the field, shouldn’t we have an answer by now?” Environmental response will be the key to finding reliable biomarkers and achieving the dream of truly personalized psychiatric medicine, she concludes. “It’s going to require doing something a little different than what we’re doing to get there.”.
