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BALTIMORE, Md. (April 14, 2023) – Modern medical research seeks to understand how genes and the environment converge on risk for most common medical disorders, from heart attack and asthma to schizophrenia and PTSD. When we think of the environment, we think of like, stress, diet and pollution. But for all the cells of our bodies, which work because of the genes within them, the environment is a molecular one. Cells don’t know about stress, diet or pollution, but they learn about them through the related changes in their molecular environment.

Investigators at the Lieber Institute for Brain Development in Baltimore and the University of Bari Aldo Moro in Bari, Italy, have explored the molecular environment of genes that have been associated with risk for schizophrenia. They examined how these schizophrenia risk genes partner with other genes in brain cells. Their findings suggest that schizophrenia risk genes need to partner with about 20 other genes in a certain way to produce illness. These 20-some genes were not previously known to play any role in schizophrenia but now appear to be novel therapeutic targets that could help prevent illness.

The scientists’ work was published on April 14 in the journal Science Advances. Read the paper.

Genes work in networks or coordinated molecular systems to make cells function. These partnerships, called gene co-expression networks, are hypothesized to contribute to turning genetic risk into the biology of risk. In their new research, Lieber Institute scientists generated computational models describing in neurotypical individuals how gene co-expression evolves in four brain regions during the life span.

The investigators found that these genes that increase risk actually change partners as the brain ages. This activity may explain why schizophrenia symptoms change over time, though the risk genes for schizophrenia do not. More importantly, the scientists discovered for the first time that there are about 20 genes that are always partnered with the schizophrenia risk genes, and these genes were not previously known to play any role in the illness.

As these models are derived from healthy subjects, they speak to the normal function of genes thought essential for schizophrenia. The research shows that these gene partnerships are altered in patients with schizophrenia, specifically in the brain region that is the principal target of currently available drugs, the dorsal striatum. This suggests that these consistent partners comprise the necessary molecular environment for the risk genes to make the cells behave in a way that leads to illness.

The authors also show that these gene relationships are found in neurons cultured in vitro from stem cells, which offers the opportunity to test gene co-expression in the lab. The importance of the finding is that these partners could be novel therapeutic targets, potentially preventing the effect of the risk genes. In principle, without these partners, there is no dance.