An international research consortium that includes researchers from the Keck School of Medicine of the University of Southern California 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.
This discovery provides 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, M.D., Ph.D., 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.
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.
Professors Michele T. Pato, M.D., Della Martin Chair in Psychiatry, and Director of the Center for Genomic Psychiatry, and Carlos N. Pato, M.D., Ph.D., Franz Alexander Professor and Chair of the Department of Psychiatry, both members of the Zilkha Neurogenetic Institute at the Keck School of Medicine of the University of Southern California (USC), led the USC team of investigators.
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.
USC’s Center for Genomic Psychiatry directs two major projects in the genetics of mental illness: the Genomic Psychiatry Cohort study and the Portuguese Island Collection. The Portuguese Island Collection was an integral population in these studies and has been done in collaboration with the University of Coimbra and the psychiatry services of the Azores and Madeira in Portugal. Other authors participating through USC include: Helena Medeiros, Frank Middleton, Celia Carvalho, Christopher Morley, Ayman Fanous, David Conti, James A. Knowles, Carlos Paz Ferreira, Antonio Macedo and M. Helena Azevedo.
“Our studies that have focused on the Portuguese Islands have been extremely fruitful in identifying these genetic factors,” says Carlos N. Pato, also chair of the Department of Psychiatry at the Keck School of Medicine of USC. “Combining the Portuguese Island populations with others from the International Schizophrenia Consortium helped define the importance of these findings.”
The most critical � and surprising � finding of the study 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 findings that show an overlap in the genomic risk for schizophrenia and bipolar disorder shed new light and hope on our understanding of the genetics of these disorders and may clarify strategies for new treatments,” says Michele T. Pato.
Thomas Insel, M.D., 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.”
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 N.I.M.H., U.K. Medical Research Council, Welcome Trust, and the Science Foundation Ireland.
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, Uller�ker, 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