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Mental disorders may share molecular origins

About one in six U.S. adults lives with a mental disorder (44.7 million in 2016). But making an accurate diagnosis can be difficult. There’s no simple test for autism spectrum disorder, schizophrenia, and other common mental disorders. It can also be difficult to know what treatments will work. A deeper understanding of the molecular processes that underlie mental disorders could lead to better diagnosis and treatment.

Most mental disorders are thought to arise from a complex mix of genetic and environmental factors. Past studies have found evidence of shared genetic risk factors among different mental disorders. A team led by Drs. Michael Gandal and Daniel Geschwind at the University of California, Los Angeles, aimed to further explore this overlap. The study, funded in part by NIH’s National Institute of Mental Health (NIMH), was published on February 9, 2018, in Science.

The scientists examined the transcriptome—the complete set of active genes (expressed RNA)—in the cerebral cortex of post-mortem brains from people with five disorders: autism spectrum disorder (50 samples), schizophrenia (159), bipolar disorder (94), depression (87), and alcoholism (17). They also compared samples from healthy matched controls (293) and people with inflammatory bowel disease (197).

The researchers found thousands of genes whose activity was elevated or suppressed in at least one of the disorders. Many were altered similarly across disorders. Others were more specific. The team found significant overlap among autism spectrum disorder, schizophrenia, and bipolar disorder. There was also overlap among schizophrenia, bipolar disorder, and depression. However, there was no significant overlap between alcoholism and any others.

The researchers next analyzed groups of genes involved in known biological processes. Among the findings was that a group of genes associated with nervous system support cells called astrocytes was up-regulated in autism spectrum disorder, schizophrenia, and bipolar disorder. Groups of genes associated with nerve cell mitochondria (the cells’ energy factories) were down-regulated across these three disorders. Genes linked to nervous system immune cells called microglia were up-regulated in autism spectrum disorder. Ones associated with inflammation were up-regulated in depression.

The scientists compared the gene expression data with genetic variations that have been previously shown to underlie disease. They found that the overlap in gene expression across the disorders corresponded to their shared genetic risks. This result reinforces the idea that there is a substantial genetic component to these mental disorders.

“We show that these molecular changes in the brain are connected to underlying genetic causes, but we don’t yet understand the mechanisms by which these genetic factors would lead to these changes,” Geschwind explains. “So, although now we have some understanding of causes, and this new work shows the consequences, we now have to understand the mechanisms by which this comes about, so as to develop the ability to change these outcomes.”

—by Harrison Wein, Ph.D.


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