Strongest single gene conclusively implicated in schizophrenia

Single-letter changes to the DNA code of one gene have been shown to have a substantial effect on the risk of schizophrenia.

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 (14 March) in Nature Neuroscience, establishes for the first time that single-letter changes to the DNA code of one gene can have such 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.

“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.”

Dr Jeff Barrett Lead author and Group Leader at the Wellcome Trust Sanger Institute

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 10 of the patients with schizophrenia, 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.

“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.”

Professor Sir Mike Owen Director of Cardiff University’s MRC Centre for Neuropsychiatric Genetics and Genomics

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

“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.”

Professor Aarno Palotie Research Director at the Institute for Molecular Medicine Finland FIMM, at the University of Helsinki

More information


* To conclusively implicate rare mutations in complex diseases requires a very large number of genomes. The SETD1A gene had previously been suggested as a candidate gene in a smaller study (Takata et al, Neuron, 2014) but too few genomes had been analysed to reach a high level of certainty. This study builds on that work, and was only possible due to the success of data sharing and collaboration in genetics.


This work was funded by the Wellcome Trust and other organisations. Please see the paper for a full list of funders.

Participating centres:

  • Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK
  • Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
  • Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge Massachusetts, USA.
  • University College London (UCL) Genetics Institute, University College London, London, UK
  • Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Please see paper for further participating centres.


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Selected websites

  • Institute for Molecular Medicine Finland (FIMM), University of Helsinki

    Institute for Molecular Medicine Finland (FIMM) is an international research institute in Helsinki focusing on human genomics and personalized medicine. FIMM is hosted by the University of Helsinki and is part of the Nordic EMBL Partnership in Molecular Medicine as well as the EU-Life network. FIMM integrates molecular medicine research, technology center and biobanking infrastructures “under one roof” and thereby promotes translational research and adoption of personalized medicine in health care. In 2015, FIMM had a staff of 200 and a budget of 17 million €, with competitive external funding accounting for a significant part of the budget.

  • Cardiff University

    Cardiff University is recognised in independent government assessments as one of Britain’s leading teaching and research universities and is a member of the Russell Group of the UK’s most research intensive universities. The 2014 Research Excellence Framework ranked the University 5th in the UK for research excellence. Among its academic staff are two Nobel Laureates, including the winner of the 2007 Nobel Prize for Medicine, University Chancellor Professor Sir Martin Evans. Founded by Royal Charter in 1883, today the University combines impressive modern facilities and a dynamic approach to teaching and research. The University’s breadth of expertise encompasses: the College of Arts, Humanities and Social Sciences; the College of Biomedical and Life Sciences; and the College of Physical Sciences and Engineering, along with a longstanding commitment to lifelong learning.

  • The Wellcome Trust Sanger Institute

    The Wellcome Trust Sanger Institute is one of the world’s leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.

  • The Wellcome Trust

    The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.