DNA variations link to schizophrenia

Research by UNC School of Medicine scientists advances understanding of the genetic basis of a debilitating mental condition.

Graphic with three portrait photos of researchers (Hyejung Won, Sool Lee and Jessica McAfee) and a molecular model of DNA.
Research by Hyejung Won (top), associate professor of genetics at the UNC School of Medicine, and graduate students Sool Lee (middle) and Jessica McAfee (bottom) is advancing the understanding of the role of genetics in schizophrenia.

Genetically speaking, we are individuals different from each other because of slight variations in our DNA sequences – so-called genetic variants – some of which have dramatic effects we can see and comprehend, from the color of our eyes to our risk for developing disease.

Now, UNC School of Medicine scientists and colleagues are figuring out which genetic variants have a causal effect in the development of schizophrenia, a debilitating psychiatric condition affecting many millions worldwide. They found that some of the genetic variants regulate or alter the expression of genes involved in the condition. This research, published in the journal Cell Genomics, marks a big step forward in the understanding of the genetic basis of schizophrenia.

“Our findings not only provide insights into the intricate regulatory landscape of genes, but also propose a groundbreaking approach to decoding the cumulative effect of genetic variants on gene regulation in individuals with schizophrenia,” said senior author Hyejung Won, associate professor of genetics at the UNC School of Medicine and member of the UNC Neuroscience Center. “This comprehension could potentially pave a path for more precise interventions and therapies in the future. Right now, therapeutic options are limited, and some people do not respond to drugs available.”

For this study, Won and first authors Jessica McAfee and Sool Lee, both UNC-Chapel Hill graduate students, led a team of researchers from UCLA, Harvard, the University of Michigan, and Human Technopole in Italy to explore the genetic variants already linked to the risk of schizophrenia. Using a special genetic sequencing technique, the researchers found 439 genetic variations with actual biological effects, meaning they can alter expression of gene.

“Traditionally, scientists have used other epigenetic data, such as transcription factor binding and biochemically defined enhancers, to identify variants with biological effects,” Won said.
“However, these conventional methods failed to predict a large portion of variants we identified to have biological effects. Our work points to a wealth of unexplored variants with biological effects.”

To understand how these variants work together to influence gene activity, Won and colleagues developed a new model that combines data from MPRA with chromatin architecture of brain cells — that is, the genetic information important for how brain cell DNA is organized. By doing this, the researchers could connect these 439 variants to how genes are turned on or off.

“Schizophrenia is a complex condition that is highly heritable,” Won said. “To find these 439 potentially causal variants is a big step, but we still have a lot of work ahead to figure out the complicated genetic architecture that leads an individual to develop this condition. With that information in hand, we could begin to understand the biological mechanism underlying this complex disorder, which may eventually lead to targeted therapies.”

This research was funded by the National Institutes of Health and the Brain and Behavior Research Foundation.

Read more about this research on the genetics of schizophrenia.