Rare Genetic Variants Implicated in the Development of Schizophrenia

When trying to discern the development of Schizophrenia in patients, doctors and scientists have a number of theories and research that they believe has charted a path to that development, and now a new one can be added to the list.

According to research from the UCL Genetics Institute genetic variants that prevent neurotransmitter receptor N-methyl-D-aspartate from working properly is implicated in the development of schizophrenia. N-methyl-D-aspartate receptor (NMDAR) is a protein that carries signals between brain cells in response to glutamate. Glutamate is one of the major neurotransmitter’s in the brain as it activates about 60% of neurons and most have a glutamate receptor. Glutamate has often been in the conversation of schizophrenia development due to its major presence in the brain along with research showing that glutamate levels are impacted by schizophrenia. Research has also shown symptoms of schizophrenia can be caused by drugs that block NMDAR.

"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," according to Professor David Curtis, UCL Genetics, Evolution & Environment, the psychiatrist who led the research.

The study, published in Psychiatric Genetics, took the DNA sequences of over 4,000 people with schizophrenia and studied the variants in the three gene codes for NMDAR, which are GRIN1, GRIN2A, GRIN2B, and FYN a protein that controls NMDAR functioning. The UCL researchers used computer programs to predict the effects of rare variants into these four genes. They found that the variants predicted to impair functioning are found in more people with schizophrenia than those without, the 5,000 controls used in the study. However, the number of variants involved are too small to draw firm conclusions, but the results are consistent with previous research that impaired NMDAR functioning produces symptoms of schizophrenia.

Professor Curtis elaborated on the results saying, “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.” The findings also support other hypothesis’ that these, and possibly other, rare genetic variants lead to abnormal NMDAR function and could increase the risk of schizophrenia in .5% of cases with these rare genetic variants.

Due to the size of this study, and nature of the rare variants, the researchers are planning a larger collaboration that will look at DNA sequence data from over 30,000 subjects with schizophrenia. Professor Curtis concluded, “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." The researchers also hope to study the effects of specific variants in model systems, like cultures of nerve cells to characterize their effects on the cell function.