In Chapel Hill, North Carolina, scientists are investigating how tiny differences in our DNA, called genetic variants, can affect our risk of getting schizophrenia. They’ve already found about 5,000 of these genetic variants linked to schizophrenia by studying the DNA of thousands of people. Now, they’re trying to determine which variants cause the condition. They’re discovering that some genetic variants can change how specific genes work in schizophrenia.
Senior author Hyejung Won, Ph.D., associate professor of genetics at the UNC School of Medicine and member of the UNC Neuroscience Center, said, “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.”
“This comprehension could pave the path for more precise interventions and therapies. Right now, therapeutic options are limited, and some people do not respond to drugs available.” the author added.
In this study, Won and graduate students Jessica McAfee and Sool Lee from UNC-Chapel Hill, researchers from UCLA, Harvard, the University of Michigan, and Human Technopole in Italy worked together. They wanted to understand which genetic variants connected to schizophrenia were crucial for the condition. This task was tricky because some variants are inherited, and not all are relevant to schizophrenia.
To solve this puzzle, they used a unique method called a ‘massively parallel reporter assay’ (MPRA). This method helps identify which variants can activate genes and which cannot. They introduced the 5,000 variants into human brain cells in a dish, which are crucial for early brain development. These variants could either turn on or off specific genes.
The Scientists used unique DNA barcodes to tell them apart. The MPRA showed that 439 of these genetic variations had a real impact on gene expression, meaning they could affect how genes work.
Scientists typically use different types of genetic data to find variants that affect genes. However, these methods should have included many variants that could be important. “Our research shows that many more of these essential variants are waiting to be discovered.” Won said.
To understand how these variants affect genes, Won and colleagues created a new model. They combined data from the MPRA with information about how DNA in brain cells is organized. This helped them to connect these 439 variants to how genes are turned on or off.
Schizophrenia is a complex condition that can run in families. Finding these 439 potential causes is a significant step. But there’s more work to understand how all these genes cause the condition.
This research holds promise for advancing an understanding of schizophrenia and, potentially, for developing more effective treatments in the future.
Journal Reference:
- Jessica C. McAfee, Sool Lee, et al., Systematic investigation of allelic regulatory activity of schizophrenia-associated common variants. Cell Genomics. DOI: 10.1016/j.xgen.2023.100404.