Endeavor Health and UChicago researchers uncover hidden genetic links to schizophrenia using active brain cells

Evanston, Ill. - Researchers from Endeavor Health and the University of Chicago have discovered new clues about how schizophrenia starts in the brain. By looking at activated brain cells instead of resting ones, they found risk factors that have been hidden until now.

Schizophrenia is a chronic brain disorder that disrupts a person's ability to think clearly, manage emotions, and relate to others. It affects millions of people worldwide - about one in 100 - and is a leading cause of disability.

The researchers' study, published in the journal Science, looked at "busy" brain cells (neurons) after they receive stimulation. The team found new genetic links to the disorder, including how the brain handles lipid and cholesterol. This helps explain why some people are at a higher risk for brain disorders than others.

"This is one of the first studies to show that by looking at activated brain cells, you can find genetic effects that were missed by just studying resting cells," said the study's leading senior author Jubao Duan, PhD, Charles R. Walgreen Research Chair and co-director of the Center for Psychiatric Genetics at Endeavor Health, and Professor of Psychiatry and Behavioral Neuroscience at UChicago.

Most diseases aren't caused by just one "impaired" gene. Instead, they happen because of a complex mix of many different genes working together. In the past, scientists studied these genes in cells that were resting or inactive.

However, many parts of our DNA act like "switches" that only turn on when the brain is triggered. To see these switches in action, the researchers grew brain cells in a petri-dish from stem cells converted from blood. They then used a common salt (potassium chloride) to "wake up" the cells and see how they reacted.

When the brain cells were thus activated, the team noticed something important: the cells from people with schizophrenia were making more genetic messengers that instruct the synthesis of cholesterol and fats than the cells from healthy people. While doctors have known for a long time that people with schizophrenia often have high cholesterol, this study shows that part of the cause might be built into their DNA.

"Our data helps us understand why certain genes are more important and when they matter most," said Xin He, PhD, a co-senior author of the study from the University of Chicago.

By understanding these "wakened" genes, the researchers believe they may find better ways to treat not just schizophrenia, but also autism and other brain-related conditions. The team plans to continue this work by studying different types of brain activity to map out even more of these hidden genetic clues.

Dr. Duan has been studying the connection between genes and brain disorders for over 20 years. He hunted for risk genes as part of Genome-wide Association Studies (GWAS) for schizophrenia, and then followed up by characterizing function risk variants in implicated risk genes. He has also studied functional risk variants in neurodegenerative disorders such as for Alzheimer's disease. He's now working to understand what neurodevelopmental risk genes such as those for schizophrenia and autism do as part of Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes (SSPsyGene), funded by the National Institutes of Mental Health.

"Our research group has spent years studying schizophrenia, including leading a major collaboration to map out its risk genes," said co-author Dr. Alan Sanders, also co-director of the Center for Psychiatric Genetics at Endeavor Health. "The current work studies how these risk genes actually function, helping clear some major hurdles and provide targets for precision treatments.".