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When the human genome was first sequenced in 2003, scientists and clinicians hoped that this complete mapping would quickly offer a better understanding of the genetic causes of common medical conditions and mental illnesses. And it certainly did—but, unfortunately, not the simple “smoking gun” single-gene discovery that might easily translate into effective treatments, especially for complex neurodevelopmental disorders (NDDs) like schizophrenia, major depressive disorder, bipolar disorder, and autism. But now, a new study suggests that looking at the genetic intersection of NDDs and commonly shared physical ailments could offer new insights into the origins of these conditions and, ultimately, help direct more effective and precise treatment.
The current Diagnostic and Statistical Manual of Mental Disorders (DSM-5, for 5th edition), published by the American Psychiatric Association, outlines the diagnostic criteria for mental disorders, including NDDs. The categories and classifications of the different disorders in the DSM-5 are based on clinical observations of symptoms, says Sarah Morris, program chief of the Schizophrenia Spectrum Disorders Research Program at the National Institute of Mental Health (NIMH).
“It’s undeniable that certain symptoms do cluster together and the categories you see in the DSM do reflect clinical reality,” she says. “But just because they are reliable doesn’t mean they are neurobiologically valid. By that I mean that we may have detected symptoms that cluster together but we may not be getting the full picture about the true nature of these disorders when we just focus on them.” (See also a Cerebrum 2011 essay by Steven Hyman, M.D.: Diagnosing the DSM: Diagnostic Classification Needs Fundamental Reform)
For one thing, the DSM-5 doesn’t highlight other symptoms that may cluster with those mental and emotional issues—the co-morbid, or shared, medical conditions that so often accompany NDDs. Most NDDs often “travel” with other medical ailments—and it’s not random what kinds of medical problems team up with NDDs, says Pat Levitt, the Simms/Mann Chair in Developmental Neurogenetics at the Institute for the Developing Mind.
“We know that many people with schizophrenia have metabolic disorders, including diabetes. Individuals with autism often have co-occurring gastrointestinal problems or cardiac disorders,” he says. “We now know that mental illnesses like schizophrenia, bipolar disorder, and autism have a developmental origin. And one explanation for why you see certain medical conditions traveling with different NDDs, and consistently doing so, is because of the genes that are involved—because genes are used in different contexts and for the development of not only the brain but other organ systems, as well. It makes sense that you’d see issues in more than one place in the body.”
Because they focus on only the brain-related symptoms and don’t take into account these comorbidities, he argues, neuroscience and other researchers may be missing important clues into how either set of issues develops.
Highlighting consistent genetic overlaps
Levitt says that clinicians have recognized the overlaps between mental and medical symptoms for some time. But, he argues, research scientists have lagged in trying to leverage known overlaps to better understand the causes of these conditions. G. Bradley Schaefer, the founding director of the division of Medical Genetics at the University of Arkansas agrees—and says such an understanding could help better inform treatments.
“In autism, we saw differential response to treatments. There would be a new treatment and people would get excited because it worked so well for a few children. But then it didn’t work at all for ninety others,” he says. “We’re learning that every person with autism probably has their own unique genetic constellation. And by looking at some of the physical symptoms, those comorbid conditions we so often see, we may get clues about what that unique genetic constellation might be.”
To show the importance of the biological relatedness of genes implicated in various NDDs with common medical co-occurrences, Levitt and colleagues analyzed more than 200 NDD risk genes to see which might be associated with other medical issues. They discovered approximately half were associated with problems with musculoskeletal, endocrine, cardiac, and genitourinary problems. Moreover, approximately one-third of those genes were linked to more than one medical issue. The results were published on Aug. 26, 2016, in Frontiers of Psychiatry.
While Levitt says his clinical experience had led him to expect some overlap, he was surprised at the degree of overlap across the NDD genes. Accounting for these overlaps offers a new framework to consider not only the development, but the treatment, of complex NDDs. By considering a more holistic approach, researchers might find clues about different pathological processes occurring before any mental symptoms ever develop. Similarly, clinicians may be able to find more effective, tailored treatments when they consider both mental and physical conditions.
“A psychiatrist or a clinical psychologist needs to pay attention to physical ailments, which may be embroidered into the fabric of the principal diagnosis of a brain-based disorder,” he says. “And they need to understand that it may require a different place of action, a different healthcare approach, to treat people who might have these kinds of overlaps. And it’s going to require a bit of a paradigm shift in the way that both researchers and clinicians think about these kinds of disorders.”
Bending the curve
While genes do not work in a vacuum, a variety of environmental and epigenetic factors have been shown to help regulate the expression of genes over the lifespan (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890560/), this kind of holistic approach to NDDs can offer new insights into both the etiology of individual disease as well as provide potential new targets for treatment. To help bring about this paradigm shift, Morris is now heading up the development of a new research framework at the NIMH called the Research Domain Criteria (RDoC). She says that despite advances in genetics and other technologies, current research platforms haven’t yielded strong results for treatment of mental illness. This new framework folds in a more holistic approach in hopes of bending the curve.
“It’s become increasingly obvious that nature is not abiding by the categories that had been defined by the DSM,” she says. “So we want to encourage people to look beyond the existing definitions of mental disorders and look at psychopathology across disorders in a different way. By taking a more integrative, holistic approach, and looking at these co-morbidities between physical and mental illness, we may uncover some really interesting clues about what the true pathophysiology might be.”
Albert La Spada, associate director for the Institute of Genomic Medicine at the University of California at San Diego, discovered a potential new treatment for Huntington’s disease by looking at some of the metabolic symptoms of the disease. He says that Levitt’s approach, as well as the RDoC framework, offer new opportunities to highlight potential new pathways for intervention. While these ideas are still at their earliest stages, and somewhat hindered by a lack of informatics and network analysis expertise to properly evaluate complex genomic data, he says, they hold a lot of promise.
“These efforts are a breath of fresh air in a field where there is a great need for new approaches to diagnosis, management, and therapy,” he says. “I expect that there will be non-neural phenotypes that do connect with neurodevelopmental syndromes, and this could be quite helpful in uncovering molecular pathology and future treatments.”