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Genetic Variants Affecting N-Methyl-D-Aspartate Receptor (NMDAR) Implicated in Development of Schizophrenia

Genetic variants that prevent a neurotransmitter receptor from working properly have been implicated in the development of schizophrenia, according to research by scientists at the University College London (UCL) Genetics Institute. The N-methyl-D-aspartate receptor (NMDAR) is a protein that normally carries signals between brain cells in response to a neurotransmitter called glutamate. Previous research has shown that symptoms of schizophrenia can be caused by drugs that block NMDAR or by antibodies that attack it. Genetic studies have also suggested that molecules associated with NMDAR might be involved in the development of schizophrenia. "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 Professor David Curtis (UCL Genetics, Evolution & Environment), the psychiatrist who is the senior author of the article reporting the recent findings. For the study, the results of which were published online on January 16, 2019 in Psychiatric Genetics, the DNA sequences of over 4,000 people with schizophrenia and 5,000 controls were used to study variants in the three genes that code for NMDAR (GRIN1, GRIN2A and GRIN2B) and a fourth (FYN), that codes for a protein called Fyn, which controls NMDAR functioning. The article is titled “In Silico Investigation of Coding Variants Potentially Affecting the Functioning of the Glutamatergic N-Methyl-D-Aspartate Receptor in Schizophrenia.” By comparing variants to the normal DNA sequence, it was possible to predict the specific rare variants that would either prevent each gene from being read or which would produce a change in the sequence of amino acids it coded for such that the protein product would not function correctly. The investigation revealed an excess of such disruptive and damaging variants in FYN, GRIN1 and GRIN2B among the people with schizophrenia.

While the numbers of variants involved are too small for firm conclusions to be drawn, the results are consistent with previous evidence that impaired NMDAR functioning can produce symptoms of schizophrenia. The results also support the hypothesis that rare genetic variants that lead to abnormal NMDAR function could increase the risk of developing schizophrenia in 0.5% of cases.

"For many years, we've been aware that drugs such as phencyclidine, which blocks the receptor, can cause symptoms just like those that occur in schizophrenia. More recently, it's been recognized that sometimes people produce antibodies that attack this receptor and, again, they have similar symptoms," said Professor Curtis.

Large genetic studies have increasingly accumulated evidence suggesting that there is an association between schizophrenia and genes associated with NMDAR, but these studies typically involve very large numbers of genes in a rather non-specific way.

The UCL researchers focused closely on just four genes and used computer programs to predict the effects of rare variants in these genes. When they did this, they found that more of the variants predicted to impair functioning are found in the people with schizophrenia than people without schizophrenia.

For example, variants in the gene for Fyn were seen in 14 schizophrenia cases and 3 controls. When the team looked at the predicted effect on the protein, they saw that all three of the variants in controls affected a region with no known function whereas 10 of the variants in schizophrenia cases occurred in functional domains of the protein.

As the variants are rare, the researchers plan on following up by studying a larger sample set. Professor Curtis is part of a collaboration that will look at DNA sequence data from over 30,000 subjects with schizophrenia.

They also plan on studying the effects of these specific variants in model systems such as cultures of nerve cells to precisely characterize their effects on the cell function.

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."

Dr. Curtis is Honorary Professor at the UCL Genetics Institute, University College London, and at the Centre for Psychiatry, Queen Mary University of London.

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[Press release] [Psychiatric Genetics abstract] [University College London (UCL)]