Genetic variants behind development of schizophrenia

A new study, led by reA new study, led by re searchers at the  UCL Genetics Institute finds that genetic variants which prevent a neurotransmitter receptor from working properly have been implicated in the development of schizophrenia.According to the study, the N-methyl-D-aspartate receptor (NMDAR) is a protein which normally carries signals between brain cells in response to a neurotransmitter called glutamate.Earlier research has shown that symptoms of schizophrenia can be caused by drugs which block NMDAR or by antibodies which attack it. Furthermore, genetic studies have also suggested that molecules associated with NMDAR might be involved in the development of schizophrenia.Speaking about it, Professor David Curtis (UCL Genetics, Evolution & Environment), the psychiatrist who carries out the research, said, “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.”For the current study, published 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 which code for NMDAR (GRIN1, GRIN2A and GRIN2B) and a fourth (FYN), for a protein called Fyn which controls NMDAR functioning.The study found that by comparing variants to the normal DNA sequence, it was possible to predict the specific rare variants which 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.The results support the hypothesis that rare genetic variants which lead to abnormal NMDAR function could increase the risk of developing schizophrenia in 0.5 per cent of cases.Large genetic studies have increasingly accumulated evidence suggesting that there is an association between schizophrenia and genes associated with NMDAR but these 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.As the variants are rare, the researchers plan on following up by studying a larger sample set.They also plan on studying the effects of these specific variants in model systems such as cultures of nerve cells to precisely characterise their effects on the cell function. (ANI)