When combined, single DNA letter difference in two separate genes may increase one’s risk for developing schizophrenia, according to Johns Hopkins researchers.
Scientists have had a difficult time pinpointing the causes for psychiatric diseases such as schizophrenia and autism, because these disorders may be triggered by several small genetic changes that alone may not trigger the disorder, but in the right combination may cause disease.
Severe DNA differences in the genetic letters of the DISC 1 gene are known to cause schizophrenia and other major mental disorders.
However, these large changes are uncommon and do not account for the majority of people with schizophrenia. Nevertheless, researchers believe DISC1 to be an entry point for studying the cause of the disease, and defects in DISC1 combined with defects in other genes may contribute to the disorder.
“We studied the function of two proteins known to interact, FEZ1 and DISC1, in cells and animal models, which suggested that these proteins work together in adult brain development,” says Guo-li Ming, M.D., Ph.D. professor of neurology and neuroscience and member of the Johns Hopkins Institute for Cell Engineering.
“When we looked at the human genetic sequences of DISC1 and FEZ1, we found that a combination of small DNA changes raises risk for schizophrenia.”
To see if FEZ1 and DISC1 work in unison in adult brain development, the scientists reduced the level of FEZ1 in newborn neurons in the hippocampi of adult mice and then evaluated the cells with a microscope. The neurons with less FEZ1 looked similar to those with less DISC1; they were bigger and had longer feelers that stretch out and communicate with other nearby neurons. The scientists hypothesized that these proteins may be working together in neurons to regulate cell size and feeler length, and if something interferes with this process, a psychiatric disease may develop.
The researchers also analyzed current cases of schizophrenia to determine if combinations of single-letter DNA changes in DISC1 and FEZ1 made individuals more prone to the disorder. The scientists examined a large patient database, the Genetic Association Information Network, created by the National Institutes of Health to identify genome associated diseases.
Using statistical methods, the researchers examined four different single-letter DNA changes in the FEZ1 sequence in 1,351 schizophrenia cases and 1,378 healthy individuals. They found that single-letter DNA changes in FEZ1 alone did not boost schizophrenia risk. However, when the scientists examined the four different FEZ1 DNA letter changes in combination with the DISC1 single DNA letter change already known to slightly increase schizophrenia risk, they discovered that one particular FEZ1 DNA difference along with the DISC1 change drastically increased the risk for schizophrenia by two and a half times.
“By continuing to examine interactions of key genes involved with disease in cells and correlating the results with patient databases, we can begin to unravel the genetic contributions of psychiatric disorders that previously were a mystery to us,” says Hongiun Song, Ph.D., professor of neurology and director of the Stem Cell Program at the Institute for Cell Engineering. “Finding sets of proteins, like FEZ1 and DISC1, that synergistically work together to cause disease will also give us new drug targets to develop new therapies.”
The research is published in the November 16 issue of Neuron.
Source: Johns Hopkins