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Circadian Expression of Genes Disrupted in Brains of Individuals With Schizophrenia

NEW YORK – Genes are often expressed rhythmically over the course of a day, but this pattern is disrupted in individuals with schizophrenia, a new study has found.

A University of Pittsburgh-led team of researchers compared post-mortem gene expression data from the dorsolateral prefrontal cortex — a region of the brain involved in cognition and memory — of nearly 50 people with and 50 people without schizophrenia. In addition to its hallmark symptoms of disordered thinking and reduced emotional expression, schizophrenia is also associated with disturbances to the sleep-wake cycle and disruptions to other diurnal patterns. 

As they reported today in Nature Communications, the researchers uncovered differences in the timing of when certain genes were expressed between the two groups.

"Our study shows for the first time that there are significant disruptions in the daily timing of when some genes are turned on or off, which has implications for how we understand the disease at a molecular level," senior author Colleen McClung, professor of psychiatry at Pitt's School of Medicine, said in a statement.

As they relied on post-mortem brain samples for their study, the researchers used a time-of-death analysis to work out the diurnal timing of when certain genes were expressed. To confirm this approach, they first analyzed RNA-seq data from 104 control individuals from the University of Pittsburgh and Mount Sinai School of Medicine to find that 19 percent of the genes they detected were rhythmic and that many of these were involved in the circadian rhythm signaling pathway or were otherwise known core circadian genes. These findings, the researchers said, were in line with what has been previously reported.

For their further analyses, the researchers used RNA sequencing data generated by the Common Mind Consortium, a public-private partnership that has developed a bank of brain tissue and data for research. When they compared 46 individuals from the dataset with schizophrenia to 46 sex- and age-matched controls, they found that both groups had about 700 rhythmically expressed genes. But only 31 of those genes overlapped between the two groups.

Among the control individuals, the rhythmically expressed genes were, again, enriched for being part of the circadian rhythm signaling pathway. But among the individuals with schizophrenia, that pathway was not enriched. 

Instead, the top enriched pathways were the oxidative phosphorylation and mitochondrial dysfunction pathways. The researchers noted, though, that some core circadian genes like CIART and CRY1 did keep their rhythmicity among individuals with schizophrenia, but with reduced amplitude.

In a statement, McClung likens this to electrical appliances in a house. "In a normal house — like a healthy brain — let's say the lights are turned on at night, but the refrigerator needs to be on all the time," she said. "What we saw was that in a schizophrenia-affected brain, the lights are on all day and the refrigerator shuts off at night." 

The researchers additionally split their schizophrenia cohort based on whether the individual died during the day or the night. When they did that, they found no difference in what genes were expressed by the individuals who died during the day and by control individuals. The difference, though, came when they compared individuals who died during the night to controls.

These differentially expressed genes are mostly involved in mitochondrial function, but also included some involved in neurotransmission or GABAergic signaling.

"If we only looked to see if the refrigerator was on during the day we would see no difference, but at night, there would be one," added first author Marianne Seney, an assistant professor of psychiatry at Pitt's School of Medicine, in a statement.

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