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   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Schizophrenia is associated with somatic mutations occurring in utero   
      
      
     Date:   
         July 6, 2023   
     Source:   
         Cell Press   
     Summary:   
         As a psychiatric disorder with onset in adulthood, schizophrenia   
         is thought to be triggered by some combination of environmental   
         factors and genetics, although the exact cause is still not fully   
         understood.   
      
         Researchers have now found a correlation between schizophrenia and   
         somatic copy-number variants, a type of mutation that occurs early   
         in development but after genetic material is inherited. This study   
         is one of the first to rigorously describe the relationship between   
         somatic -- not inherited -- genetic mutations and schizophrenia   
         risk.   
      
      
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   As a psychiatric disorder with onset in adulthood, schizophrenia is   
   thought to be triggered by some combination of environmental factors and   
   genetics, although the exact cause is still not fully understood. In a   
   study published in the journal Cell Genomics on July 6, researchers find   
   a correlation between schizophrenia and somatic copy-number variants,   
   a type of mutation that occurs early in development but after genetic   
   material is inherited. This study is one of the first to rigorously   
   describe the relationship between somatic -- not inherited -- genetic   
   mutations and schizophrenia risk.   
      
   "We originally thought of genetics as the study of inheritance. But now we   
   know that genetic mechanisms go way beyond that," says senior author Chris   
   Walsh, an investigator at the Howard Hughes Medical Institute and chief   
   of genetics and genomics at Boston Children's Hospital. "We're looking   
   at mutations that are not inherited from the parents."  The researchers   
   analyzed genotype-marker data from over 20,000 blood samples of people   
   with or without schizophrenia from the Psychiatric Genomics Consortium.   
      
   They ultimately identified two genes -- NRXN1and ABCB11 -- that correlated   
   with schizophrenia cases when disruptedin utero. NRXN1, a gene that   
   helps transmit signals throughout the brain, has been associated with   
   schizophrenia before.   
      
   However, this is the first study to associate somatic, not inherited,   
   NRXN1 mutations with schizophrenia.   
      
   Unlike inherited mutations, which are present in all the cells of the   
   body, somatic mutations are only present in a fraction of cells based   
   on when and where a mutation occurred. If a mutation occurs early in   
   development, it is expected that the variant is present throughout the   
   body in a mosaic pattern.   
      
   On the basis of 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 cells in the blood.   
      
   "If a mutation occurs after fertilization when there are only two cells,   
   the mutation will be present in half of the cells of the body," says   
   Walsh. "If it occurs in one of the first four cells, it will be present   
   in about a quarter of the cells of the body, and so on."  The second   
   gene the researchers identified, ABCB11, is most known to encode a liver   
   protein. "That one came out of nowhere for us," says Eduardo Maury, a   
   student in Harvard-MIT's MD-PhD program. "There have been some studies   
   associating mutations in this gene with treatment-resistant schizophrenia,   
   but it hasn't been strongly implicated in schizophrenia per se."  When the   
   team investigated further, they found that ABCB11is 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 individual's 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 patient's   
   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."   
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   Journal Reference:   
      1. Eduardo A. Maury et al. Schizophrenia-associated somatic copy-number   
         variants from 12,834 cases reveal recurrent NRXN1 and ABCB11   
         disruptions.   
      
         Cell Genomics, 2023; 100356 DOI: 10.1016/j.xgen.2023.100356   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/07/230706124520.htm   
      
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