An international research consortium has discovered that many common genetic variants contribute to a person's risk of schizophrenia and explain at least a third of the risk of inheriting the disease, providing the first molecular evidence that this form of genetic variation is involved in schizophrenia. The researchers also found that many of these DNA variations also are involved in bipolar disorder but not in several non-psychiatric diseases. The findings, reported by the International Schizophrenia Consortium and published online in the journal Nature, represent a new way of thinking about the genetics of psychiatric diseases, which seem to involve not only rare variants but also a significant number of common ones as well.
"While our study finds a surprising number of genetic effects, we fully expect that future work will assemble them into meaningful pathways that will teach us about the biology of schizophrenia and bipolar disorder," says Pamela Sklar, MD, PhD, of the Massachusetts General Hospital (MGH) Department of Psychiatry and Center for Human Genetic Research (CHGR), a senior associate member of the Broad Institute of MIT and Harvard and corresponding author of the Nature paper.
Co-corresponding author Shaun Purcell, PhD – also of MGH Psychiatry and the CHGR, and an associate member of the Broad Institute – emphasizes that "how these genetic variants translate into schizophrenia or bipolar disorder for a given patient is not yet known." Sklar and Purcell stress that, although these results are remarkably robust and give insight into the underlying genetics of these diseases, they cannot currently be used as a diagnostic test or to predict an individual's personal risk.
Schizophrenia is a common and often devastating brain disorder characterized by persistent delusions and hallucinations. It affects about 1 percent of the world's population and usually strikes in late adolescence or early adulthood. Despite the availability of treatments, the course of the illness is usually chronic, and response to treatments is often incomplete, leading to prolonged disability and personal suffering. Family history, which reflects genetic inheritance, is a strong risk factor for both schizophrenia and bipolar disorder, and it has generally been assumed that dozens of genes, along with environmental factors, contribute to disease risk.
Formed in 2006, the International Schizophrenia Consortium is led by senior researchers from 11 institutes in Europe and the USA. Major funding and resources for the current work were provided by the Broad Institute's Stanley Center for Psychiatric Research. Equally crucial to the success of the project was the willingness of consortium groups to share thousands of patient DNA samples collected over many years.
In the current study, the researchers tested hundreds of thousands of genetic variants (single nucleotide polymorphisms) in more than 3,300 individuals with schizophrenia and 3,600 individuals without the disorder. The work used novel analytical techniques based on theoretical models developed by consortium members Naomi Wray, PhD, and Peter Visscher, PhD, of the Queensland Institute of Medical Research, Brisbane, Australia.
The most critical – and surprising – finding was that the same large group of genetic variants was more common in all groups of schizophrenia patients, even though the DNA samples were collected by different investigators and tested in different laboratories. The additional discovery that these schizophrenia-related variants were also common in people with bipolar disorder was particularly striking, since the two disorders are considered to be distinct, although related, conditions.
"The consortium has taken important steps towards unearthing the complex genomic architecture of schizophrenia and other psychotic disorders, and this paper is another example of that critical work," said Edward Scolnick, MD, director of the Stanley Center for Psychiatric Research at the Broad Institute. "To fulfill the promise of these early studies, we as a community will need to continue to fully define the genetic basis of these disorders and ensure that our insights help improve the diagnostic and therapeutic options for patients and their families."
Thomas Insel, MD, director of the National Institute for Mental Health, which partially funded the study, adds, "These new results recommend a fresh look at our diagnostic categories. If some of the same genetic risks underlie schizophrenia and bipolar disorder, perhaps these disorders originate from some common vulnerability in brain development."
Professor Ian Hickie – executive director of consortium member the Brain and Mind Research Institute, University of Sydney, Australia – says, "This is a key study from both a conceptual and a practical perspective. It provides striking evidence for the common genetic risk factors for the major psychiatric disorders. The race will now focus on identification of the key neurodevelopmental genes that underpin these disabling conditions."
The study was supported by grants from the Stanley Medical Research Foundation through the Stanley Center for Psychiatric Research, and the Sylvan Herman Foundation. Other major funding bodies include the U.K. Medical Research Council, Wellcome Trust, and the Science Foundation Ireland.
About Massachusetts General Hospital
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine. For more information, visit www.massgeneral.org.
About the Broad Institute of MIT and Harvard
The Eli and Edythe L. Broad Institute of MIT and Harvard was founded in 2003 to empower this generation of creative scientists to transform medicine with new genome-based knowledge. The Broad Institute seeks to define all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.
Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to www.broad.mit.edu.
Institutional Members of the International Schizophrenia Consortium
Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland
MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, Wales
School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, Scotland
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Department of Psychiatry, Center for Human Genetic Research, Massachusetts General Hospital,
Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill
Queensland Institute of Medical Research, Queensland, Australia
Center for Genomic Psychiatry, University of Southern California, Los Angeles
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Mass.
Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Ireland
Department of Mental Health Sciences, University College London Medical School, Windeyer Institute of Medical Sciences, London, England
Additional international contributors include:
The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Department of Neuroscience, Psychiatry, Ulleråker, Uppsala University, Uppsala, Sweden
Department of Medical Genetics, University Hospital Maichin Dom, Sofia, Bulgaria
Department of Psychiatry, First Psychiatric Clinic, Alexander University Hospital, Sofia, Bulgaria
Molecular and Cellular Therapeutics and RCSI Research Institute, Royal College of Surgeons in Ireland, Dublin, Ireland
West Berkshire NHS Trust, Reading, England
West London Mental Health Trust, Hammersmith and Fulham Mental Health Unit and St. Bernard's Hospital, London, England
Queen Mary College, University of London and East London and City Mental Health Trust, Royal London Hospital,Whitechapel, London, England
Ravenscraig Hospital, Greenock, Scotland
State University of New York – Upstate Medical University, Syracuse, N.Y.
Washington VA Medical Center, Washington, D.C.
Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.
Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia
Department of Psychiatry, Sao Miguel, Azores, Portugal
Department of Psychiatry, University of Coimbra, Coimbra, Portugal
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