Live-cell model system can decode genetic risk for psychiatric disorders

For many years, scientists have known that genetic variants, or differences in DNA code across people, play some role in neurological and psychiatric disorders. But the details were murky. Now, researchers at the UNC School of Medicine are using a combination of cell lines and DNA sequencing approaches to look closely at our genomes and identify which genetic variants and genes play roles in influencing one’s risk for neurological and psychiatric disorders.

A research team led by Jason Stein, Ph.D., associate professor of genetics and member of the UNC Neuroscience Center, has used a live-cell model system of the human brain to identify the function of genetic variants important for increasing the risk of developing schizophrenia, autism spectrum disorder, and bipolar disorder. The results were published in Nature Neuroscience.

“There are hundreds of different locations on our genome that are associated with psychiatric disorders,” said Stein, who is also a member of UNC Lineberger Comprehensive Cancer Center. “But these locations are in regions of the genome where the function is not well understood. We supposed that some genetic variants function only when stimulated by certain neural pathways important for brain development.”

Out of our entire genome, just 3% is responsible for creating codes that lead to the formation of proteins—the “machines” that perform needed tasks in our bodies. The other 97% of the genome does not code for proteins. It is in these “non-coding” regions where most genetic variants implicated in psychiatric illness can be found.

Non-coding variants are expected to be similar to light switches. They can “turn on” and “turn off” genes that code for proteins. But finding the precise function of these non-coding genetic variants has proven difficult for researchers. This is because “non-coding” genetic variants can have a “context-dependent” function, which means they only work when specific cellular pathways are stimulated. In other words, the downstream effects of these genetic variants can only be observed when brain cells are alive and responding to stimulation.

The Stein lab decided to study the function of these genetic variants in neural progenitor cells, which are cells involved in brain development. Every cell line has a different genetic background, which allows researchers to compare and contrast genetic variants in both active and inactive states. Stein’s lab members exposed the stem cells to different chemical compounds and controls to measure the differences in response.

These compounds stimulate the Wnt pathway, a cascade of proteins that play important roles in brain development. Using the living model, researchers found thousands of non-coding genetic variants that have a context-dependent function.

“Through the activation of Wnt-responsive genes, we found variants with context-dependent function that are implicated in schizophrenia risk,” said Stein. “Finding these genetic variants represents an important step forward in our understanding of the mechanisms that cause someone to be at greater risk of developing a neuropsychiatric disorder.”

Stein said that a similar study design using this live-cell model system of the human brain could be helpful for testing how genetic variation influences risk for environmental exposures, like lead exposure, and their impacts on the brain. Similarly, future applications of this approach could be used to prescribe psychiatric treatments based on an individual’s genetics.

Co-first authors on the study were research associate Nana Matoba, post-doctoral fellow Brandon D. Le, and graduate student Jordan M. Valone.