Breakthrough in schizophrenia research: hidden culprits are somatic genetic mutations

A new research study has revealed a correlation between schizophrenia and somatic copy number variant gene mutations that occur after inheritance. This marks one of the initial studies to demonstrate a link between somatic mutations and schizophrenia risk.

A study a Cell genomics found a link between somatic gene mutations and schizophrenia. The researchers analyzed more than 20,000 blood samples, identifying the NRXN1 and ABCB11 genes as associated with schizophrenia when disrupted during fetal development. The finding highlights the role of non-inherited gene mutations in psychiatric disorders, and the team plans to explore other potential associated mutations.

As an adult-onset psychiatric disorder, schizophrenia is thought to be triggered by a combination of environmental and genetic factors, although the exact cause is not yet fully understood. In a study published in the journal Cell genomics On July 6, researchers found a correlation between schizophrenia and somatic copy number variants, a type of mutation that occurs early in development but after the genetic material has been inherited. This study is one of the first to rigorously describe the relationship between nonheritable somatic gene mutations and schizophrenia risk.

We originally thought of genetics as the study of heredity. But we now know that the genetic mechanisms go much further, says senior author Chris Walsh, a research scientist at the Howard Hughes Medical Institute and chief of genetics and genomics at Boston Childrens Hospital. We’re looking at mutations that aren’t inherited from parents.

The researchers analyzed genotypic marker data from more than 20,000 blood samples from people with and without schizophrenia from the Psychiatric Genomics Consortium. Eventually they identified two genesNRXN1 AND ABCB11which was related to cases of schizophrenia when discontinued in the uterus. NRXN1, a gene that helps transmit signals throughout the brain, has previously been associated with schizophrenia. However, this is the first study to associate somatic, not hereditary, NRXN1 mutations with schizophrenia.

Schizophrenia-associated somatic copy number variants from 12,834 cases reveal recurrent disruptions of NRXN1 and ABCB11. Credit: Cell Genomics / Maury et al.

Unlike inherited mutations, which are present in all cells of the body, somatic mutations are present in only a fraction of cells based on when and where a mutation occurred. If a mutation occurs early in development, the variant is expected to be present throughout the body in a mosaic pattern. Based on this principle, researchers can identify somatic mutations that occurred early in development and are present not only in the brain but also in a fraction of blood cells.

If a mutation occurs after fertilization when there are only two cells, the mutation will be present in half of the body’s cells, Walsh says. If it occurs in one of the first four cells, it will be present in about a quarter of the cells in the body, and so on.

The second gene identified by the researchers, ABCB11, it is best known for encoding a liver protein. That came out of nowhere for us, says Eduardo Maury, a Harvard undergraduate-[{” attribute=””>MITs MD-PhD program. There have been some studies associating mutations in this gene with treatment-resistant schizophrenia, but it hasnt been strongly implicated in schizophrenia per se.

When the team investigated further, they found that ABCB11 is also expressed in very specific subsets of neurons that carry dopamine from the brainstem to the cerebral cortex. Most schizophrenia drugs are thought to act on these cells to decrease an individuals dopamine levels, so this might explain why the gene is associated with treatment resistance.

Next, the team is working towards identifying other acquired mutations that might be associated with schizophrenia. Given that the study analyzed blood samples, it will be important to look at more brain-specific mutations that might have been too subtle or recent in a patients life for this analysis to detect. In addition, somatic deletions or duplications might be an under-investigated risk factor associated with other disorders.

With this study, we show that it is possible to find somatic variants in a psychiatric disorder that develops in adulthood, says Maury. This opens up questions about what other disorders might be regulated by these kinds of mutations.

Reference: Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions by Eduardo A. Maury, Maxwell A. Sherman, Giulio Genovese, Thomas G. Gilgenast, Tushar Kamath, S.J. Burris, Prashanth Rajarajan, Erin Flaherty, Schahram Akbarian, Andrew Chess, Steven A. McCarroll, Po-Ru Loh, Jennifer E. Phillips-Cremins, Kristen J. Brennand, Evan Z. Macosko, James T.R. Walters, Michael ODonovan, Patrick Sullivan and Psychiatric Genomic Consortium Schizophrenia and CNV workgroup, 6 July 2023, Cell Genomics.
DOI: 10.1016/j.xgen.2023.100356

This work was supported by the Harvard/MIT MD-PhD program, the Biomedical Informatics and Data Science Training Program, the Ruth L. Kirschstein NRSA F31 Fellowship, the National Institutes of Health, the Stanley Center for Psychiatric Research, the Brain Somatic Mosaicism Network, the Psychiatric Genomics Consortium, the Allen Discovery Center for Human Brain Evolution, the Howard Hughes Medical Institute, the Suh Kyungbae Foundation, and the Chan Zuckerberg Initiative and Scientific Interfaces. The authors declare no conflicts of interest.