Study uncovers surprisingly diverse genome alterations contributing to schizophrenia

A multinational group of investigators has discovered that people suffering from schizophrenia are far more likely to carry rare chromosomal structural changes of all types, particularly those that have the potential to alter gene function. In addition, the study uncovered two new specific genomic areas that, when altered, significantly increase the risk of developing the disease. The report from the International Schizophrenia Consortium, the largest and most complete such study to date, is being published online today by the journal Nature.

Schizophrenia is a common, chronic and often devastating brain disorder characterised by delusions and hallucinations. It affects approximately 1 person in 100 at some point in their lives and usually strikes in late adolescence or early adulthood. Despite the availability of effective treatments, the course of the illness is usually chronic, and response often limited, leading to prolonged disability and personal suffering. Family history, which signifies genetic inheritance, is the strongest risk factor for schizophrenia, but until now little has been known about the specific genes or chromosome regions involved.

'This surprising excess of many types of chromosomal changes in schizophrenia patients provides us with rich clues to follow up in future research,' says Pamela Sklar, MD, PhD, of the Department of Psychiatry and Centre for Human Genetic Research at Massachusetts General Hospital (MGH), a Senior Associate Member of the Broad Institute of MIT and Harvard and corresponding author of the Nature paper. 'This work opens up an entirely new way to think about schizophrenia and eventually will suggest new avenues for researching effective therapies for the sake of patients and families suffering from this terrible disorder.'

Formed in 2006, the International Schizophrenia Consortium is led by senior researchers from 11 institutes in Europe and the USA (see complete list below). The research team was coordinated by Sklar, who is also Director of Genetics at the Stanley Centre for Psychiatric Research at the Broad Institute, which provided the major funding and research resources for the current work. Equally crucial to the success of the project was the willingness of consortium groups to pool DNA resources that have taken them years to collect, totalling 3,391 individuals with schizophrenia and 3,181 related individuals without the disorder.

The investigators used new genomic technologies and novel analytical techniques developed at the Broad Institute and at MGH to screen these samples for structural variants in the genome, sites where a portion of a chromosome is missing or duplicated. This unprecedented scale of cooperation allowed the analysis of enough data to identify schizophrenia-specific genome alterations - including the newly identified sites on chromosomes 1 and 15 and an area on chromosome 22 observed in earlier studies - as well as a subtle general increase in structural genomic variants in schizophrenia patients compared with controls. A second study also being published in Nature today confirms the association of those three genomic sites with increased risk for developing the disease.

'The Consortium should be recognised for taking the important first step towards unearthing the full underlying genomic architecture of schizophrenia and other psychotic disorders,' says Edward Scolnick, MD, Director of the Stanley Centre for Psychiatric Research at the Broad Institute. 'Only by doing such a large study could we have uncovered these stunning findings to such a high degree of confidence, thus setting the stage for an even more complete understanding of the full genomic contributions to disease. This study could only have been done with the open collaboration of many individuals and institutions dedicated to understanding - and treating - this terrifying disease.'

Thomas Insel, MD, director of the National Institute for Mental Health, which partially funded the study, adds,'By implicating two previously unknown sites, this study triples the number of genomic areas definitely linked to schizophrenia. It also confirms in a large sample that unravelling the secrets of rare structural genetic variation may hold promise for improved diagnosis, treatment and prevention of such neurodevelopmental disorders.'

Lead analyst Shaun Purcell, PhD, of the MGH Department of Psychiatry and Centre for Human Genetic Research and an Associate Member of the Broad Institute at the Stanley Centre, emphasises that 'the specific way a small overall increase in this kind of genetic variation translates into schizophrenia for a given patient is not yet known, especially given the common occurrence of these structural genomic variations in everyone.'

Professor Michael O'Donovan, FRCPsych, PhD, of Cardiff University in Wales, notes, 'The findings are impressive and hugely important leaps towards understanding the origins of schizophrenia. But since only a small amount of the genetic risk for schizophrenia has been accounted for, they are not ready to be applied to genetic testing, an area that has seen fierce controversy as a number of biotech companies have begun offering genetic tests for psychiatric disorders.

The study was supported by grants from the Stanley Medical Research Foundation through the Stanley Centre for Psychiatric Research, the National Institute of Mental Health and the Sylvan Herman Foundation. Other major funding bodies include the Wellcome Trust, the Science Foundation Ireland and the UK Medical Research Council. Along with Purcell, Sklar's co-authors at MGH and the Stanley Centre include Jennifer Stone, PhD, Joshua M. Korn, Steven McCarroll, PhD, Douglas Ruderfer, Mark Daly, PhD, Kimberly Chambert, Casey Gates, Stacey Gabriel, PhD, Scott Mahon and Kristen Ardlie, PhD.