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Schizophrenia Risk Genes Coexpressed Differently Across Lifetime, Brain Regions

NEW YORK – Researchers at Johns Hopkins University and the University of Bari in Italy have found that coexpression of various genes involved in schizophrenia changes with age and differs between brain regions, helping to explain the onset of clinical disease symptoms.

"While the genes that are involved in schizophrenia tend to stay together, we show that these genes change their partners across different age groups. We think this is the reason that the clinical manifestations change" with age, said co-corresponding author Daniel Weinberger, director of the Lieber Institute for Brain Development at Johns Hopkins.

While previous genome-wide association studies have highlighted hundreds of genes that confer schizophrenia risk, it has been largely unclear how these genes converge into biological pathways that manifest in symptoms of schizophrenia, he added.

For their study, published in Science Advances on Friday, Weinberger and colleagues looked at coexpression levels of schizophrenia risk genes and other genes across different age groups and brain regions, using RNA sequencing data from 833 post-mortem brain samples. These included 562 brains from neurotypical controls from European and African American individuals and 186 brains from schizophrenia patients. The study focused on specific brain areas, in particular the dorsolateral prefrontal cortex (DLPFC), hippocampus, caudate nucleus, and dentate gyrus.

The researchers found that the risk genes were coexpressed differently across samples, depending on the age of the individuals. "Parsing by age periods explained more variance in a score of gene importance for [schizophrenia] compared to lumping all age periods together in a single network," the authors wrote.

Using computational methods, they additionally found a new set of 28 genes that were consistently coexpressed with schizophrenia risk genes in the DLPFC, of which 24 had not been implicated in schizophrenia in previous GWAS studies. "We think these are the critical molecular environments that schizophrenia genes need to be in the neighborhood of," Weinberger said.

These genes could be studied in the future to develop new drug targets, he said, noting that most of the current drugs to manage schizophrenia target dopamine pathways.

They also found that schizophrenia risk genes tend to be most convergently expressed prenatally, especially in the frontal cortex.

Highlighting the limitations of the research, Weinberger said that this work needs to be replicated in other datasets.

"And finally, we need to change the activity of some of these newly identified genes and show that they really disrupt the effect that schizophrenia genes have on risk," he added.