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    Home > Biochemistry News > Biotechnology News > Back to back two "Nature": Milestones!

    Back to back two "Nature": Milestones!

    • Last Update: 2022-04-16
    • Source: Internet
    • Author: User
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    A new view of schizophrenia as a disruption of communication at synapses


    In a landmark genetics study of more than 121,000 people, an international consortium called SCHEMA, led by researchers at the Broad Institute of MIT and Harvard, has identified 10 genes that are extremely rare protein-disrupting mutations that greatly increase an individual's risk of developing schizophrenia -- more than 20-fold in one case


    Taken together, these studies underscore the novel idea that schizophrenia is a disruption of synaptic (the connections between neurons) communication, and illustrate how different types of genetic variants affecting the same gene can affect the risk of different psychiatric and neurodevelopmental disorders


    a global collection

    The SCHEMA and PGC findings are the result of a 10-year push by researchers at the Stanley Center and nearly 40 other institutions around the world


    The two research groups have followed complementary paths in the study of the genetics of schizophrenia


    The Schizophrenia Exome Meta-Analysis Consortium (SCHEMA), established in 2017, focuses on the exome, the nearly 2 percent of the genome that encodes proteins


    "These studies contain 10 years of data," said Sinéad Chapman, who, along with team members Christine Stevens, Caroline Cusick and many others, spent hundreds of hours ensuring that samples and data from SCHEMA collaborators were processed appropriately and tracking for these analyses


    Using whole-exome sequencing of 24,248 people with schizophrenia and 97,322 people without schizophrenia, the SCHEMA team identified extremely rare variants in 10 genes that greatly increase a person's risk of developing schizophrenia risk


    Benjamin Neale, PGC collaborator, institute member and director of genetics at the Stanley Center, co-director of the institute's medical and population genetics programs, and ATGU faculty member at Massachusetts General Hospital, said: Both have about a 1 percent chance of developing schizophrenia


    Their findings also hint at 22 additional genes that may influence schizophrenia risk, which may prove important after further research


    Taken together, these genes point to dysfunction at synapses (where neurons connect and communicate with each other), which may be a cause of schizophrenia


    A closer look at two of the 10 genes in the SCHEMA study, GRIN2A and GRIA3, further suggests that synapses are a key part of the mechanistic roots of schizophrenia


    However, most SCHEMA genes have never been associated with brain disorders or neuron-specific functions


    These genes will eventually lead to some new insights, but a lot of follow-up experiments will be needed to pinpoint their place in the puzzle


    In addition, the PGC team examined common genetic variants in 76,755 people with schizophrenia and 243,649 people without schizophrenia and found 287 regions of the genome (or loci) associated with schizophrenia risk, an increase from a previous study published in 2019.


    The PGC team also found that the genomic regions they implicated are primarily active only in neurons, and only in the brain, and affect mechanisms that directly affect neuron function, such as synaptic structure and organization
    .

    The nature and effects of the variants detected by PGC differ in some respects from the SCHEMA findings
    .
    For example, the destructive protein-coding GRIN2A mutation identified in SCHEMA is extremely rare and increases the risk of schizophrenia 24-fold
    .
    The variant found in the PGC study was more common and altered the expression of GRIN2A, increasing the risk by only 1.
    06-fold
    .

    However, the fact that the findings of the two studies brought together similar groups of genes and similar biological mechanisms suggests that genetic discoveries are beginning to focus on core aspects of the biology of schizophrenia, and are close to understanding the progression of schizophrenia A broader understanding of the mechanism
    .

    Scientists call this an overlapping relationship between synaptic biology and schizophrenia risk
    .

    Lessons from sharing risk

    The SCHEMA data also shed light on how psychiatric and neurodevelopmental disorders share genetic risk more broadly
    .
    For example, several SCHEMA genes, including GRIN2A, were previously implicated in neurodevelopmental conditions such as epilepsy, developmental delay and intellectual disability
    .

    By sequencing the whole exomes of 24,248 people with schizophrenia and 97,322 people without schizophrenia, the SCHEMA team identified extremely rare variants in 10 genes that significantly increase a person's risk of developing schizophrenia risk
    .
    These variants, known as "protein truncation variant" PTVs, prevent cells from producing the gene's full-length functional protein
    .

    "We found that different kinds of mutations in the same gene have a range of consequences," Neale noted.
    "We
    still have a lot to do about the role of these genes, the variation in those genes, and the biological consequences of genetic variation, and There are many things to know
    .
    "

    "This is critical for gaining insights into how genes play a role in brain disease, and we need to make sure we don't take an isolated view of this data, but keep an open mind and learn what these genetics teach us in phenotypes things
    .
    "

    In fact, this view is already bearing fruit
    .
    In a separate study published in the journal Nature Genetics, members of the International Bipolar Disorder Exome Consortium (BipEx), including Neale, report how a comparison of SCHEMA and BipEx data helped reveal the AKAP11 gene Genes in rare PTVs that increase the risk of bipolar disorder several-fold
    .
    This makes it the strongest genetic risk factor for bipolar disorder ever identified
    .

    put the puzzle together

    "Mental illness has been a black box for a long time
    .
    Unlike cardiovascular disease or cancer, we have few biological clues about the mechanism of disease," said Tarkin, a postdoctoral fellow at the Broad Institute's Stanley Center for Psychiatry Research.
    Tarjinder Singh said
    .
    "As a result, we lack the insight necessary to develop much-needed new treatments
    .
    Instead, we've been repeatedly researching antipsychotic drugs that were discovered by chance more than 70 years ago
    .
    " Singh, who is also in the Department of Analytical and Translational Genetics at Massachusetts General Hospital ( ATGU), he is a collaborator on the PGC study and co-corresponding author of the SCHEMA study
    .

    "Identifying these 10 genes was a watershed moment in schizophrenia research, as each of them provided a solid foundation for initiating biological research," Neale said
    .
    "By sequencing the DNA of thousands of people, we're starting to see exactly which genes are important
    .
    These findings are a starting point for developing new therapies to treat the underlying causes of this devastating disease
    .
    "

    A lot of work has been done to simulate the effects of SCHEMA mutations in the laboratory
    .
    The researchers also recognize that there are many other genetic discoveries yet to be discovered
    .

    "These first 10 genes are just the beginning of gene discovery," Neale said
    .
    "There is fairly clear evidence that many more genes can be found with the same method
    .
    But we need a larger sample size to reveal these additional genes
    .

    "However, if you have more pieces of the puzzle," he continued, "it may be easier to put them together into a more coherent mechanistic view of schizophrenia and how we might approach these processes, with a view to Improve the lives of patients
    .
    "

    "The biological complexity of schizophrenia is truly daunting, but this combination of rare protein-altering variants from exome sequencing and common variants from GWAS sets us on the path to understanding the roots of this complexity.
    On the road, with these results, we may see how synaptic abnormalities or loss in schizophrenia begin, giving us the opportunity to diagnose and treat patients at an earlier time than is currently possible
    .
    "

    "With schizophrenia, as with other complex disorders, I think we'll end up finding many processes involved in risk or protection, and understanding that is probably one of the most complex tasks in genetics and biology
    .
    "

    Steven Hyman, a core member of the Broad Institute and director of the Stanley Center, said: "We have been trying for many years to gain this kind of traction in the biology of schizophrenia
    .
    It will take much longer for these results to translate into biomarkers and treatments that will change the lives of people living with this devastating disease
    .
    But there is a compelling path forward that is very motivating
    .
    "

    Both studies were made possible because the necessary pieces were finally in place, Singh said
    .
    He said: "Genomic technologies, sequencing infrastructure, and the computational tools needed to understand the data they produce, have advanced tremendously over the past 20 years
    .
    The most important part is the global commitment of PGC and SCHEMA members, both institutionally and nationally.
    Share samples and data to reach the number of people needed to reveal these rare mutations
    .
    "

    Article title:

    Rare coding variants in 10 genes confer substantial risk for schizophrenia

    10.
    1038/s41586-022-04556-w


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