New Study Finds Genetic Link Between Somatic Mutations and Schizophrenia Risk
A new research study published in Cell Genomics has revealed a correlation between schizophrenia and somatic copy-number variants (CNVs)—genetic mutations that occur post-inheritance. This groundbreaking study marks one of the initial findings to demonstrate a link between somatic mutations and the risk of developing schizophrenia.
Researchers conducted a comprehensive analysis of over 20,000 blood samples, identifying two specific genes, NRXN1 and ABCB11, that are associated with schizophrenia when disrupted during fetal development. NRXN1, a gene involved in transmitting signals throughout the brain, has been previously linked to schizophrenia. However, this study is the first to establish a connection between somatic mutations in NRXN1 and the development of the disorder.
Additionally, the researchers unexpectedly discovered that ABCB11, a gene primarily known for encoding a liver protein, also played a role in schizophrenia. Further investigations revealed that ABCB11 is expressed in specific subsets of neurons involved in dopamine transmission, which is targeted by many schizophrenia drugs. This finding may explain why the gene is associated with treatment resistance in schizophrenia cases.
Somatic mutations differ from inherited mutations as they only exist in a fraction of cells, dependent on when and where the mutation occurred. This mosaic pattern of mutation distribution indicates whether the mutation appeared early or later in development. If a mutation occurs shortly after fertilization, it is likely to be present in about a quarter of the body’s cells.
Lead author Chris Walsh, an investigator at the Howard Hughes Medical Institute, explains, “We originally thought of genetics as the study of inheritance. But now we know that genetic mechanisms go way beyond that. We’re looking at mutations that are not inherited from the parents.”
The research team plans to further investigate other acquired mutations associated with schizophrenia, focusing on identifying brain-specific mutations that may have been too subtle or recent to be detected in blood samples. They believe that somatic deletions or duplications may play a significant role in the risk of developing various disorders, which has yet to be thoroughly explored.
“This study demonstrates that it is possible to detect somatic variants in a psychiatric disorder that develops in adulthood,” says Eduardo Maury, a student in Harvard-MIT’s MD-PhD program. “This opens up questions about what other disorders might be regulated by these kinds of mutations.”
The findings of this study contribute to the growing understanding of the complex genetic mechanisms underlying schizophrenia and highlight the importance of considering non-inherited mutations in the development of psychiatric disorders. The research lays the groundwork for future investigations into the role of somatic mutations in various disorders, potentially leading to new insights and treatment strategies.
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
The study was supported by various programs and institutions including 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, and the Howard Hughes Medical Institute, among others. The authors of the study declare no conflicts of interest.