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Gene Copy Number Changes and SchizophreniaMissing or Extra DNA on Chromosomes 1 and 15 Can Lead to Schizophrenia by Dr. Barry Starr, Stanford UniversityAugust 8, 2008  Schizophrenia is a devastating mental illness. And yet, schizophrenia is surprisingly common. Around 1% of the U.S. population suffers from this disease. If a close relative like a parent or a brother or sister has schizophrenia, then someone’s chances of getting it are around 10%. And if an identical twin has schizophrenia, then the other twin’s chances of getting it are 50%! Numbers like these suggest that genes are a big part of schizophrenia. Two new studies have found that genes on chromosomes 1 and 15 may play a big role in causing at least some cases of schizophrenia. In any event, they almost certainly are involved in some very rare cases. There are a couple of interesting findings with these results. First, the changes are not subtle. Huge regions of DNA containing many different genes are missing or duplicated in many of the patients with schizophrenia that these studies looked at. These kinds of differences are called copy number variations or CNVs. Another interesting finding is that these differences aren’t found in the parents. At some point between making an egg or sperm and the first few cell divisions of the fertilized egg, chunks of DNA went missing. Or were duplicated. Researchers are finding these sorts of genetic differences more and more often. These particular changes may explain only a small percentage of schizophrenia cases. Combining both studies, only around 20 out of thousands of schizophrenia cases are explained. These are not a lot of cases. But they can point researchers in the right direction for where to look in other patients. Maybe researchers will be able to find more common and more subtle ways to get schizophrenia by looking more closely at these same regions. The Two Studies
Copy Number Variation Genes are the recipes for proteins that keep our minds and bodies running properly. For example, there are proteins that carry our oxygen. And proteins that help nerves carry our thoughts. If something goes wrong with a protein, then it can’t do its job as well. Then that person can end up with sickle cell anemia. Or schizophrenia. There are many ways for a protein to end up not working right. One way is if the instructions for making the protein change. This can happen when parts of the gene get duplicated or go missing. Or when one or a few of the DNA letters in the gene change. Another way to cause a protein not to work the same is to make more or less of it. For the human body to work well, it needs just the right amount of all of its proteins. When there is too much or too little of a protein, then things can get out of whack. The amount of protein can be affected by small changes in the DNA near the gene. Or by having missing or extra copies of the whole gene. In the cases studied here, the amount of protein went down because copies of genes were lost. In other words, big pieces of DNA went missing in these patients. Gene Copy Number Can Change Between Generations Copy number changes are much more common than people thought even a few years ago. In one study, researchers found an average of 600-900 copy number variations (CNVs) per person. Most of these are passed down from parent to child but new ones do appear occasionally. When this happens, the child can now end up with a disease that the parents and the parents’ family never had. This has been shown to be important in some cases of autism. And now it has been shown to be important for schizophrenia too. More InformationCNV on Chromosomes 1 and 15 Increase Schizophrenia Risk up to 15-fold Both studies used microarrays to find DNA changes associated with schizophrenia. Both studies used microarray technology to find the regions with a CNV. Microarrays are simply a way to look at many spots on DNA at once. Study 1: In the first study, the authors propose that because schizophrenia is so severe, it must not be easily passed down. But because schizophrenia appears to be genetic, these changes must happen in the individual and not be passed on to the child. So the researchers started out by looking at the DNA of parents and their children. What they were looking for was CNVs that appeared in the children that were not in the parent. When they looked at 33,250 such people, they found 66 CNVs that were in the children but not their parents. The researchers then looked at people with schizophrenia to see if any of the CNVs were common in them. They next compared the DNA of 1433 patients with schizophrenia to 33,250 people without the disease. They found that eight of the CNV differences could be found in the schizophrenia patients. They also found that three of the CNVs happened more often than the other five. Next they looked for these three CNVs in more people with schizophrenia. They found that these three CNVs happened much more frequently in the 3,285 patients with schizophrenia compared with the 7,951 without it. Of these three CNVs, two were much more significant than the other one. The results:
These data show that these CNVs while significant, are not very common. Study 2: In the second study, the authors proposed that people with schizophrenia will have, on average, more CNVs than people without schizophrenia. The first step was to compare the DNA of 3,391 patients with schizophrenia to 3,181 related people without schizophrenia. They found that CNVs were somewhat more common in patients with schizophrenia. People without schizophrenia had an average of 0.99 CNVs/person. People with schizophrenia had 1.15. Further analysis showed that people with schizophrenia were over 3.5 times more likely to have a large deletion compared to people without schizophrenia. The researchers then looked more closely at their results and found two regions more commonly deleted in people with schizophrenia. Their results are below:
Again, these data show that these CNVs while significant, are not very common. Next Steps The results from these two studies show that schizophrenia can result from rare genetic changes that happen between generations. There are a number of interesting next experiments to come out of these studies. The first is for the researchers to home in on the regions they found. Are there more subtle DNA changes associated with schizophrenia that are found in these regions? Which if any of the 27 genes in 1q21.1 is involved in schizophrenia? Which genes in 15q13.3 are involved? The second is to figure out whether 15q11.2 is important or not. This can be determined by looking at more samples. Another interesting next experiment will be to watch the people who did not have schizophrenia but have the deletions. Do they develop schizophrenia later in life? These first steps were an important advance. Now the real work can begin. Content provided by the Department of Genetics, Stanford University. |
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