Being a psychiatric disorder that begins in adulthood, it is believed that the schizophrenia is triggered by a combination of environmental and genetic factors, although the exact cause is not yet fully understood.
In one study, researchers found a correlation between schizophrenia and somatic copy number variants, a type of mutation that occurs early in development but after genetic material has been inherited. This study is one of the first to rigorously describe the relationship between somatic, non-hereditary genetic mutations.
The results of research were published in the journal Cell Genomics.
Correlation between schizophrenia and somatic variants: here are the results of the study
“We initially thought of genetics as the study of heredity. But now we know that genetic mechanisms go far 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 are looking at mutations that are not 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. They eventually identified two genes – NRXN1 and ABCB11 – that were related to cases of s. when interrupted in utero. NRXN1, a gene that helps transmit signals throughout the brain, has previously been linked to schizophrenia. However, this is the first study to associate somatic, non-hereditary, NRXN1 mutations with s.
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 the 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 in the early stages of development and that 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 the cells in 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 in the body, and so on.”
The second gene identified by the researchers, ABCB11, is best known for encoding a liver protein. “That came out of the blue for us,” says Eduardo Maury, a Harvard-MIT MD-Ph.D student. plan. “There have been some studies associating mutations in this gene with treatment-resistant schizophrenia, but it has not 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 transport dopamine from the brainstem to the cerebral cortex. Most schizophrenia drugs are thought to act on these cells to reduce an individual's dopamine levels, so this could explain why the gene is associated with treatment resistance.
Next, the team is working to identify other acquired mutations that may be associated with schizophrenia. Because the study analyzed blood samples, it will be important to look at more specific brain mutations that may have been too subtle or recent in a patient's life to be detected by this analysis. Furthermore, somatic deletions or duplications may be an understudied risk factor associated with other disorders.
“With this study we demonstrate 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 types of mutations.”
Schizophrenia is a neurodevelopmental disorder that disrupts brain activity producing hallucinations, delusions, and other cognitive impairments. Researchers have long looked for genetic influences in the disease, but genetic mutations have only been identified in a small fraction – less than a quarter – of patients sequenced. A new study now shows that “somatic” genetic mutations in brain cells could explain some of the neuropathology of the disease.
The study, conducted by senior author Jeong Ho Lee, M.D., Ph.D., at the Korea Advanced Institute of Science and Technology and the Stanley Medical Research Institute team, appears in Biological Psychiatry.
Traditional genetic mutations, called germline mutations, occur in sperm or eggs and are passed on to offspring from parents. Somatic mutations, in contrast, occur in an embryo after fertilization and can appear throughout the body or in isolated pockets of tissue, making them much more difficult to detect in blood or saliva samples, which are typically used for such studies. sequencing.
Recently, more advanced genetic sequencing techniques have allowed researchers to detect somatic mutations, and studies have shown that even mutations present at very low levels can have functional consequences. A previous study had suggested that somatic brain mutations were associated with schizophrenia (SCZ), but it was not powerful enough to cement that association.
In the current study, the researchers used deep whole-exome sequencing to determine the genetic code of all exomes, the parts of genes that code for proteins. The scientists sequenced post-mortem samples from 27 people with schizophrenia and 31 control participants from both brain and liver, heart or spleen tissue, allowing them to compare the sequences in the two tissues.
Using a powerful analytical technique, the team identified an average of 4.9 somatic single nucleotide variants (SNVs), or mutations, in brain samples from people with SCZ and 5.6 somatic SNVs in brain samples from control subjects
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Although there was no significant quantitative difference in somatic SNVs between SCZ and control tissues, the researchers found that mutations in SCZ patients were found in genes already associated with SCZ. Of the germline mutations previously associated with schizophrenia, the genes affected coding proteins associated with synaptic neural communication, particularly in a region of the brain called the dorsolateral prefrontal cortex.
The researchers then determined which proteins might be affected by the newly identified somatic mutations. Surprisingly, a protein called GRIN2B was highly affected, and two SCZ patients had somatic mutations on the GRIN2B gene itself. GRIN2B is a protein component of NMDA-type glutamate receptors, which are critical for neural signaling. Defective glutamate receptors have long been suspected of contributing to SCZ pathology; GRIN2B is one of the most studied genes in schizophrenia.
John Krystal, MD, editor of Biological Psychiatry, said of the work: “The genetics of schizophrenia have been studied intensively for several decades. Now a new possibility emerges that in some cases, mutations in the DNA of brain cells contribute to the biology of schizophrenia.
Surprisingly, this new biology points to an old story of schizophrenia: NMDA glutamate receptor dysfunction. Perhaps the pathway by which somatic mutations contribute to schizophrenia converges with other sources of abnormalities in glutamate signaling in this disorder.
Dr Lee and team next wanted to evaluate the functional consequences of the somatic mutations. Because of the location of the GRIN2B mutations found in SCZ patients, researchers hypothesized that they might interfere with the localization of receptors on neurons.
Experiments on mouse cortical neurons showed that the mutations actually disrupted the normal localization of receptors on dendrites, the “listening” ends of neurons, which in turn prevented the formation of normal synapses in the neurons. The finding suggests that somatic mutations could disrupt neural communication, contributing to SCZ pathology.
The somatic mutations identified in the study had a variant allele frequency of only about 1%, indicating that the mutations were rare among brain cells as a whole. However, they have the potential to create widespread cortical dysfunction.
Dr Lee said of the findings: “In addition to the comprehensive genetic analysis of brain mutations alone in post-mortem tissues of schizophrenia patients, this study experimentally showed the biological consequences of the identified somatic mutations, which led to toneuronal abnormalities associated with schizophrenia . Therefore, this study suggests that somatic brain mutations may be an important hidden contributor to SCZ and provides new insights into the molecular genetic architecture of schizophrenia.”
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