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Strongest Single Gene Conclusively Implicated in Schizophrenia

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An international consortium of researchers, led by a team at the Wellcome Trust Sanger Institute, has discovered conclusive evidence for the involvement of a gene called SETD1A in schizophrenia.  Damaging changes to this gene, which occur rarely, increase the risk of schizophrenia 35-fold and also increase risk for a wide range of neurodevelopmental disorders.

The research, published today in Nature Neuroscience, establishes for the first time that single-letter changes to the DNA code of one gene can have such a substantial effect on the risk of schizophrenia, leading to a step forward in understanding the biology and potential treatments of schizophrenia.

Schizophrenia is a devastating mental illness affecting nearly 300,000 people in the UK, but knowledge of what causes it is very limited. Previous studies of families have shown that genetics plays an important role in the disorder.

Researchers found that mutations that remove the function of the SETD1A gene are almost never found in the general population, and affect less than 1 in 1000 people with schizophrenia. While this gene explains only a very small fraction of all schizophrenia patients, it provides an important clue to the wider biology of the disorder.

Dr Jeff Barrett, lead author and Group Leader at the Wellcome Trust Sanger Institute said: “The results were surprising, not only that we found such a high level of certainty that the SETD1A gene was involved, but also that the effects of the gene were so large. Psychiatric disorders are complex diseases involving many genes, and it is extremely difficult to find conclusive proof of the importance of a single gene. This is a really exciting finding for research into schizophrenia.”

In the largest study of its kind to date, the genome sequences of more than 16,000 people from the UK, Finland and Sweden were analysed, including those from 5,341 people who had been diagnosed with schizophrenia.

Damage to the SETD1A gene was found in ten of the schizophrenia patients, and surprisingly was also found in 6 other people with other developmental and neuropsychiatric disorders such as intellectual disability. This finding that the same gene is involved in both schizophrenia and developmental disorders shows that they may share common biological pathways. 

Professor Sir Mike Owen, Director of Cardiff University’s MRC Centre for Neuropsychiatric Genetics and Genomics, said:  “We have a very limited understanding of how schizophrenia arises, and this has hampered attempts to develop new treatments. Current drugs are only effective in alleviating some of the symptoms, can lead to troubling side effects, and are ineffective in a sizeable minority of cases. Defects in the SETD1A gene, which by itself explains only a small fraction of cases, may guide us towards new pathways that could be targets for therapeutic drugs in a larger number of cases.”

The study* incorporates new DNA sequence data and builds upon eight published studies, one of which previously suggested SETD1A as a candidate susceptibility gene.

Professor Aarno Palotie, Research Director at the Institute for Molecular Medicine Finland FIMM, at the University of Helsinki said: “To get this level of certainty about the involvement of rare genes requires a huge collaborative effort.  Four International consortia have contributed data to this study, with hundreds of researchers and thousands of patients over 30 years. Collaborations like this pave the way for large-scale analyses over the next couple of years that could really explain the genetic basis of schizophrenia.”