Small changes in the sequence of the gene that encodes for a neurotransmitter receptor have been linked to the development of schizophrenia. This receptor and the molecule it binds - N-methyl-D-aspartate (NMDA), have already been linked to the disorder. Drugs that block the NMDA receptor (NMDAR) can cause symptoms of schizophrenia, and genetic research has indicated that NMDAR-associated molecules play a role in schizophrenia development. The new study, by scientists at the University College London (UCL) Genetics Institute, has been reported in Psychiatric Genetics.
"These results, and others which are emerging, really focus attention on abnormalities in NMDAR functioning as a risk factor for schizophrenia. Given all the pre-existing evidence it seems tempting to conclude that genetic variants, which by one means or another reduce NMDAR activity, could increase the risk of schizophrenia," said psychiatrist and professor David Curtis of UCL Genetics, Evolution & Environment, who carried out the research.
In this work, scientists focused on the genes that encode for NMDAR - GRIN1, GRIN2A and GRIN2B and the gene for the Fyn protein - FYN, which regulates the function of NMDAR. They assessed gene sequences in 4,000 schizophrenia patients and 5,000 unaffected control sequences.
Small variations in the genes enabled the researchers to identify changes that would cause a detrimental change in the NMDAR protein or one that rendered it nonfunctional. Disruptive changes were found in the schizophrenia patients in the GRIN1, GRIN2B and FYN genes. The findings support the hypothesis that variations in genes that are related to NMDAR function raise the risk of schizophrenia, but only in about 0.5 percent of cases.
"For many years we've been aware that drugs such as phencyclidine, which blocks the receptor, can cause symptoms just like those which occur in schizophrenia. More recently it's been recognized that sometimes people produce antibodies which attack this receptor and again they have similar symptoms," said Curtis.
While other genetic studies have indicated that NMDAR-linked genes are connected to schizophrenia, they have often involved large numbers of genes. This work zeroed in on a small group of genes and showed that people with schizophrenia tended to have more variants that were predicted to cause dysfunction.
Variations in the Fyn gene were identified in fourteen schizophrenia patients and three unaffected controls. The controls carried changes that were predicted to have no impact on the function of the resulting protein, however, in the schizophrenia patients, ten of the variations were in important parts of the protein - functional domains.
The researchers only identified a handful of variations, so they want to follow up on this work. Curtis is working with collaborators to assess 30,000 more patients.
"Currently available medications for schizophrenia are not directed at NMDAR. However if we can conclusively demonstrate ways in which its function is abnormal then this should further stimulate attempts to develop new drugs which target this system, hopefully leading to safer and more effective treatments,” said Curtis.
Learn more about the connection between NMDAR and schizophrenia from the video.