Overlap in genes altered in schizophrenia, autism, intellectual disability

Dublin, Ireland and Cold Spring Harbor, NY – In research published today in Molecular Psychiatry, a multinational team of scientists presents new evidence supporting the theory that in at least some cases of schizophrenia, autism and intellectual disability (ID), malfunctions in some of the same genes are contributing to pathology.

The team, the product of an ongoing collaboration between Professors W. Richard McCombie of Cold Spring Harbor Laboratory (CSHL) and Aiden Corvin of Trinity College, Dublin, studied a type of gene aberration called de novo mutation, in a sample of 42 “trio” families in which the child, but neither parent, was diagnosed with schizophrenia and/or psychosis and 15 trio families with a history of psychosis.

Schizophrenia is thought to be caused in many instances by gene mutations passed from parents to children, the effects of which may be enhanced by adverse environmental factors. In contrast, de novo mutations, or DNMs, are gene defects in offspring that neither parent possesses. They are the result of mechanical DNA copying errors, and occur infrequently in every human being during sperm and egg development, typically with no overall impact on human health.

However, on rare occasions, de novo mutations occur in a gene or genes indispensable for normal development and thus can have devastating consequences. This may be true of several of the genes affected by DNMs that are described in the newly published research. According to Shane McCarthy, Ph.D., a CSHL research investigator who is lead author of the new study, three genes found among the 42 affected children in the study – AUTS2, CDH8 and MECP2 – have been identified in prior genetic studies of people with autism. Two others, HUWE1 and TRAPPC9, have turned up in studies of people with intellectual disability.

Of these five “overlapping” genes, three (CHD8, MECP2 and HUWE1) have convergent function. They play roles in what scientists call the epigenetic regulation of transcription. That is, they are involved in the reading, writing and editing of chemical marks (called epigenetic marks) on DNA and proteins that help control when particular genes are switched on or off.

This makes the discovery particularly interesting, because “there’s a growing awareness of the importance of epigenetic regulation during brain development, as well as in cognition in the mature brain,” McCarthy points out. It is possible, the team speculates, that the genes found to affect the same biological function in multiple disorders are examples of those upon which normal brain development depends.

“Research made possible by the CSHL-Trinity College collaboration is leading us toward a much better understanding of how complex sets of genes are involved in complex illnesses,” says McCombie, who is director of the Stanley Institute for Cognitive Genomics at CSHL. “Our work and that of other researchers, when taken together, is beginning to clarify our view of causation in these very complex, but also very common illnesses.”

The Stanley Institute is dedicated to discovering the genetic causes of bipolar disorder, schizophrenia, depression and other cognitive disorders. The Institute’s collaboration with Trinity College Dublin has the broader goal of integrating genetics, neurobiology and clinical application in order to impact current and future treatment of mental illness.

Professor McCombie notes that many genes can contribute to complex disorders such as schizophrenia. The challenge for scientists, he explains, is that “the number of differences between even healthy individuals is so great that finding which specific variant might contribute to a specific disorder such as schizophrenia from among those that don’t cause problems, is difficult.”

The team’s newly published study narrows down the search to a portion of the human genome called the exome. This is the small fraction – some 3%-4% of the total human genome sequence – that contains protein-encoding genes. This strategy is especially useful in comparing children with their parents, because children have very few genetic variants – de novo mutations, by definition — that are not in one or the other parent. “Finding de novo variants in a child compared to their parents is technically relatively simple,” says McCombie, and presents scientists with a particularly strong “signal” of potentially significant genetic variation in children who have an illness like schizophrenia that is not evident in either parent.

McCarthy adds, “In contrast to other methods of exploring the genome for genetic variation underlying schizophrenia risk, the granularity of exome sequencing enables us to identify specific genes that may be involved in the pathogenesis of the illness. This provides us with new biological insights into the disease that could be targeted with novel therapeutics to treat not just schizophrenia but a range of psychiatric disorders.

6 thoughts on “Overlap in genes altered in schizophrenia, autism, intellectual disability”

  1. I agree with previous comments about the fact that this is an amazing discovery and will most likely change the way we perceive and treat mental disability, but I must agree with Inge that the way this knowledge is put to use will be a critical factor.

    As seen in history, the concept of Eugenics is quite a fragile one. Trying to better our own race with the “best” genes and removing the “bad” genes. Parents only want the best for their children and will try to have the best possible future for their children.

    Will screening for these de novo mutations become common place, like way we test for heart and lung defects and Down’s syndrome? Will gene therapy start as soon as the foetus is diagnosed with a mental illness? Or will the parents opt to wait for their child to show signs that there is a problem, before continuing with such drastic approaches? This will trigger the question of nature versus nurture, where the parents might think mental illness might be caused by other environmental factors and not just genes.

    This is a profound finding and will change the way we treat most illnesses and I am quite excited for people who suffer from these illnesses, as they might finally be able to live the life they want.

  2. It is amazing how a small change can have such a huge effect on who you turn out to be. Even if they can discover exactly what to change in the DNA sequence so that there will not be any physiological defects, the article itself mentioned that its not the gene alone that causes the defect, but that the surrounding environment plays a big role in how the child will turn out. So maybe it wont be necessary to change the DNA sequence itself but just use this information to determine which children are at risk and to ensure that they are raised in the right environment This means that this study can be of value to everyone, even religious people who do not approve of genetic treatment.

    I honestly hope that this study can continue even if the results wont be used for genetic manipulation to prevent physiological disorders like ID(and I hope they can use it) but just to help recognize the at risk groups.

  3. With my previous knowledge of Genetics, I assumed that when an individual has a genetic disorder that neither of the parents possesses, it is because both parents carried a recessive allele for that disorder. One of each parent is therefore needed to be expressed by the new individual.

    I now understand that some genetic disorders, such as autism or schizophrenia are in some cases caused by de novo genetic mutations.

    As I understand, the reason why neither parents showed any sign of psychiatric disorders, is that the gene mutation was not part of the parents’ genomes at all. The mutation took place during meiosis for germ cell development in one of the parents. The mutated germ cell makes up a half of the new individual’s genome, (the other half coming from the other parent) and the mutation is expressed as a psychiatric disorder in the new individual.

    This is a very exciting discovery. Now that scientists know where to look for the genes that cause some of the psychiatric disorders, it is also easier for them to possibly develop cures for it.

  4. I find the whole concept of de novo mutations, or DNMs to be very fascinating. I can’t help but link it to the Genetics that we are being taught as part of our Molecular and Cell Biology module.
    Even with all our DNA’s efforts to correct any errors that may occur during Transcription, there are still slip ups that occur. I think that down playing the mutations that occur by saying that insignificant genes are effected is not the best approach. If mutations spontaneously occur during foetal development then it is bound to eventually effect the genes that actually result in feasible differences in the child’s physical or mental state.

    The way I understand it, the parents provide the child with a sort of template DNA that is then able to influence the child’s DNA but it is not the exact genetic coding of the child’s DNA. The child’s DNA will then be a result of both parents DNA in addition to some variation that occurs in the form of mutations. So DNMs are the result of the child’s own variations to the DNA it receives from its parents.

    I think that genetic mutations such as the de novo mutations are part of our evolutionary process and are primarily a result of the environmental conditions that we are being exposed to. So the possibility that our environment is causing mental disorders among our offspring is an indication of the negative effect we must be having on our environments.

  5. Although I do agree with Cara that it is amazing to discover the intricate nature of DNA and the shocking consequences of even the tiniest mutation in a gene, I am somewhat concerned about what the researchers plan to do with this knowledge.

    I can only assume that they intend to use this knowledge for gene therapy so that they will be able to replace or repair the DNM’s of the patients. However, several ethical concerns spring to mind.

    Firstly, will religious patients opt for this treatment? Many devout Christians are currently opposing this treatment as they believe that it is ‘playing god’. If a large amount of patients reject treatment or refuse to fund this project, will its success not be severely compromised?

    Secondly, who will chaperon the use of eugenics? As with most things, humans have a tendency to do what they please and only consider the consequences afterwards. It is more than possible that gene therapy may worsen the physical condition of the patient. Since it requires the use of a vector, gene therapy can result in cancer, destruction of healthy cells, cause infection or result in an unwanted immune response. If this project is undertaken it is necessary that it is done carefully so that possible side effects are minimal.

    That being said, I believe that this is a new and interesting development in the treatment of mental disorders. I really do wish both scientists well and send them my congratulations.

  6. It still amazes me how something as little as a nano-sized gene can have such a large influence on a human being! Let alone be the cause of an intellectual disability, schizophrenia or autism…

    A child’s genome consists out of half of each parent’s DNA. In contrast, the de novo mutations are not found in the genetic material of either parent of an individual with these defective genes. The mutations occur after birth in the individual on their own. However, will the individual with, for example schizophrenia caused by de novo mutations, be able to transfer this “overlapping” genes to his or her children and result in having children with schizophrenia, autism or an intellectual disability?

    Also, genes are not always the cause for certain changes in the human body. Are these mutations triggered by certain environmental factors?


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