Researchers Identify Correlation Between Schizophrenia and Somatic Mutations

A correlation between schizophrenia and somatic copy-number variants—a type of mutation that occurs early in development, but after genetic material is inherited—has been identified by Harvard Medical Institute researchers. The study is among the first to describe the relationship between somatic (not inherited) genetic mutations and risk for schizophrenia.

Findings from the study were published in the journal Cell Genomics.

“We originally thought of genetics as the study of inheritance, but now we know that genetic mechanisms go way beyond that,” study senior author Chris Walsh, an investigator at the Howard Hughes Medical Institute and chief of genetics and genomics at Boston Children’s Hospital, said in a news release. “We’re looking at mutations that are not inherited from the parents.”

For the study, genotype-marker data from more than 20,000 blood samples of people—both those with and without schizophrenia—were analyzed, a process that resulted in 2 genes showing a correlation with schizophrenia when disrupted in utero. The first gene, NRXN1, helps transmit signals to the brain. While NRXN1 previously has been associated with schizophrenia, the Harvard study was the first to associate somatic mutations of the gene with schizophrenia. 

Researchers found that the second gene, ABCB11, primarily known to encode a liver protein, is expressed in specific subsets of neurons carrying dopamine from the brainstem to the cerebral cortex. Because most schizophrenia medications are thought to act on these cells to decrease dopamine levels, researchers theorized that it could explain why the gene is associated with treatment resistance.

Researchers who worked on the study said they will focus next on identifying other acquired mutations that could be associated with schizophrenia. 

“With this study, we show that it is possible to find somatic variants in a psychiatric disorder that develops in adulthood,” Eduardo Maury, a student in the Harvard-MIT MD-PhD program, said. “This opens up questions about what other disorders might be regulated by these kinds of mutations.”

Reference

Maury EA, Sherman MA, Genovese G, et al. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions. Cell Genom. 2023;3(8). doi.org/10.1016/j.xgen.2023.100356

Schizophrenia is associated with somatic mutations occurring in utero. News release. Cell Press. July 6, 2023. Accessed October 18, 2023.