The cerebral cortex has both shared and distinctive gene activity patterns in patients with major mental disorders.

CNRI/SCIENCE SOURCE

Major mental illnesses unexpectedly share brain gene activity, raising hope for better diagnostics and therapies

Mental illness affects one in six U.S. adults, but scientists' sense of the underlying biology of most psychiatric disorders remains nebulous. That's frustrating for physicians treating the diseases, who must also make diagnoses based on symptoms that may only appear sporadically. No laboratory blood test or brain scan can yet distinguish whether someone has depression or bipolar disorder, for example.

Now, however, a large-scale analysis of postmortem brains is revealing distinctive molecular traces in people with mental illness. This week, an international team of researchers reports that five major psychiatric disorders have patterns of gene activity that often overlap but also vary in disease-specific—and sometimes counterintuitive—ways. The findings, they say, might someday lead to diagnostic tests and novel therapies, and one has already inspired a clinical trial of a new way to treat overactive brain cells in autism.

Outsiders say the data mark a milestone in psychiatry. "This [work] is changing fundamental views about the nature of psychiatric illness," says Kenneth Kendler, a psychiatric geneticist at Virginia Commonwealth University in Richmond.

Researchers have long known that genes influence mental illness. Five years ago, for example, the global Psychiatric Genomics Consortium found that people with autism, schizophrenia, bipolar disorder, depression, and attention-deficit hyperactivity disorder frequently share certain DNA variations. But that 2013 study did not say how those genetic alterations might lead to symptoms.

Dan Geschwind, a neurologist and neuroscientist at the University of California, Los Angeles (UCLA), who spearheaded the new work, wanted to know what happens at the molecular level in the brains of people with these disorders. He, his UCLA colleague Mike Gandal, and their team analyzed gene expression patterns from the cerebral cortex, the brain's outer layer, of 700 postmortem patients with autism, schizophrenia, bipolar disorder, depression, or alcoholism and compared the patterns with those from the brains of 293 matched healthy controls. For another control, they also looked at cortical gene expression in 197 patients with inflammatory bowel disease, which should help exclude general disease processes shared by non–central nervous system conditions.

The analysis revealed that certain psychiatric diseases are more similar biologically than their characteristic symptoms indicate. Bipolar disorder is commonly considered a mood disorder, like depression, so it stands to reason that the underlying biology of both ailments would be comparable. But the genomic data told a different story: Bipolar disorder overlapped the most in cortical gene activity with schizophrenia. "This is not what clinicians would've expected," Kendler says. "It certainly suggests the idea that these are sharply different kinds of disorders is not valid."

In another surprise, Geschwind, Gandal, and their colleagues found essentially zero correlation in gene activity patterns between alcoholism and the other four disorders. Many studies in identical twins, who have largely identical DNA, had suggested that the genetic risk factors for major depression and alcohol use disorder are similar, Kendler says. Yet the new work suggests that's not the case.

Another series of tantalizing findings hinted at autism's molecular roots. The study showed, for example, that many genes in the cerebral cortex are active in both schizophrenia and autism—but they are far more active in autism. The finding suggests that gene overexpression might play a role in autism's symptoms. Meanwhile, genes linked to neuronal firing were turned down in autism, as well as in schizophrenia and bipolar disorder—suggesting that changes in brain cell communication play a role in all three conditions.

Another cluster of gene activity that stood out in autism points to overactive microglia, a subset of brain immune cells that protect against inflammation. Based on that, Gandal is leading a small clinical trial that will test whether an antibiotic can keep these cells in a resting state in adults with autism.

Jordan Smoller, a psychiatric geneticist at Harvard Medical School in Boston who led the 2013 study of genetic variants in mental disorders, says the field needs to dive even deeper than the new work by focusing on gene expression from single cells, rather than the large brain area examined in the current analysis. That could help researchers zero in on specific cell types driving the disorders, he suggests.

Nonetheless, Smoller applauds the trend in psychiatric genomics toward large consortia that can tackle big problems with masses of data. "The message [from the new study] is a broadly hopeful one," Kendler adds. "We're beginning to see the bits of the puzzle starting to slowly get clearer."