Somatic Genetic Mutations Unveiled as Key Players in Schizophrenia Research Breakthrough

In a groundbreaking research study, the connection between schizophrenia and somatic copy-number variants (CNVs), genetic mutations that occur after inheritance, has been revealed. This study represents a significant step forward in understanding the link between somatic mutations and the risk of schizophrenia.

Published in Cell Genomics, a study has identified a strong association between somatic genetic mutations and schizophrenia. Researchers meticulously examined more than 20,000 blood samples, pinpointing the genes NRXN1 and ABCB11 as being linked to schizophrenia when disrupted during fetal development. This finding sheds light on the role of non-inherited genetic mutations in psychiatric disorders, prompting the research team to explore additional potential associated mutations.

Schizophrenia, a psychiatric disorder that manifests in adulthood, is believed to be triggered by a combination of genetic factors and environmental influences, although the precise cause remains incompletely understood. A study recently published in the journal Cell Genomics on July 6 has found a correlation between schizophrenia and somatic copy-number variants, a specific type of mutation that occurs early in development but after the inheritance of genetic material. This study is among the first to comprehensively describe the relationship between somatic—rather than inherited—genetic mutations and the risk of schizophrenia.

“We initially viewed genetics solely through the lens of inheritance. However, we now know that genetic mechanisms extend far beyond that,” explains senior author Chris Walsh, an investigator at the Howard Hughes Medical Institute and chief of genetics and genomics at Boston Children’s Hospital. “We are examining mutations that are not inherited from parents.”

The research team analyzed genotype-marker data from over 20,000 blood samples obtained from individuals both with and without schizophrenia, sourced from the Psychiatric Genomics Consortium. Eventually, they identified two genes, NRXN1 and ABCB11, which demonstrated a correlation with schizophrenia when disrupted during early development. NRXN1, a gene involved in transmitting signals throughout the brain, has been previously associated with schizophrenia. However, this study is the first to link somatic, non-inherited NRXN1 mutations with schizophrenia.

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

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

The second gene identified by the researchers, ABCB11, is primarily known for encoding a liver protein. “That discovery took us by surprise,” says Eduardo Maury, a student in Harvard-MIT’s MD-PhD program. “Some studies have linked mutations in this gene to treatment-resistant schizophrenia, but it has not been strongly associated with schizophrenia itself.”

Further investigation revealed that ABCB11 is also expressed in highly specific subsets of neurons responsible for carrying dopamine from the brainstem to the cerebral cortex. Most schizophrenia medications are believed to act on these cells, reducing an individual’s dopamine levels, which may explain why this gene is associated with treatment resistance.

Moving forward, the research team aims to identify other acquired mutations that could be linked to schizophrenia. Given that the study analyzed blood samples, it is crucial to investigate more brain-specific mutations that may have been too subtle or recent in a patient’s life to be detected in this analysis. Additionally, somatic deletions or duplications might be underexplored risk factors associated with other disorders.

“With this study, we demonstrate the possibility of identifying somatic variants in a psychiatric disorder that develops in adulthood,” Maury concludes. “This raises questions about what other disorders might be influenced by these types 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 O’Donovan, Patrick Sullivan, and Psychiatric Genomic Consortium Schizophrenia and CNV workgroup, 6 July 2023, Cell Genomics.
DOI: 10.1016/j.xgen.2023.100356

This work received support from 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.

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More about schizophrenia research

• Cell Genomics: Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions
• Psychiatric Genomics Consortium
• Howard Hughes Medical Institute
• Boston Children’s Hospital
• Harvard-MIT MD-PhD Program
• National Institutes of Health
• Stanley Center for Psychiatric Research
• Brain Somatic Mosaicism Network
• Allen Discovery Center for Human Brain Evolution
• Suh Kyungbae Foundation
• Chan Zuckerberg Initiative and Scientific Interfaces