A new study by a large international consortium found that many common genetic variants contribute up to a third of a person's risk of inheriting schizophrenia and many of the same DNA variations are also involved in bipolar disorder. While the study helps to explain the complexity of the genetic make up of these diseases it also suggests that developing a test to predict these diseases will take some time.

The study, which provides the first molecular evidence of this form of genetic variation in schizophrenia and shows a new way of thinking about the genetic origins of psychiatric diseases, was the work of the International Schizophrenia Consortium whose members are drawn from 26 different research centers in the US, Europe and Australia. The findings are published as an advance access paper on 1 July in the journal Nature.

Dr Thomas Insel, director of the National Institute for Mental Health, which partially funded the study, said:

"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," he added.

The researchers found that not only are rare variants involved, but also a significant number of common ones.

Dr Pamela Sklar, of the Massachusetts General Hospital (MGH) Department of Psychiatry and Center for Human Genetic Research (CHGR), and a senior associate member of the Broad Institute of MIT and Harvard, is a corresponding author of the paper. She said that:

"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."

Dr Shaun Purcell is also a corresponding author of the paper and with MGH Psychiatry and the CHGR, and an associate member of the Broad Institute. He said that while they now know the variants, they don't know how they translate into into schizophrenia or bipolar disorder for a given patient.

However, while the results are remarkable and robust, both Sklar and Purcell point out that they are not enough from which to develop a diagnostic test to predict a particular person's risk of inheriting these diseases.

For this study, the researchers examined hundreds of thousands of single nucleotide polymorphisms (SNPs, discrete sections of DNA that contain the genetic variants) from over 3,300 individuals with schizophrenia and 3,600 individuals without the disorder. They used new analytical methods developed by consortium members from the Queensland Institute of Medical Research in Brisbane, Australia: Drs Naomi Wray and Peter Visscher.

To their surprise, and perhaps the most critical finding of the study, was the discovery that the same large group of SNPs was common to all the samples from schizophrenia patients, even though these had been collected by different researchers and tested in different labs.

Another striking discovery was the fact these schizophrenia-related variants were also common in people with bipolar disorder but not to several non-psychiatric diseases. The two disorders are considered distinct but related conditions, the researchers said.

The authors wrote that this study provides:

"Molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect."

The International Schizophrenia Consortium was set up in 2006 and much of the funding comes from the Broad Institute's Stanley Center for Psychiatric Research. The success of the project relies on the willingness of its members to share DNA samples taken from thousands of patients over many years.

Director of the Stanley Center for Psychiatric Research at the Broad Institute, Dr Edward Scolnick, said:

"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."

"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," he added.

The Brain and Mind Research Institute at the University of Sydney is another consortium member in Australia. Their executive director, Professor Ian Hickie said this research:

"Reveals striking evidence for the common genetic risk factors behind the major psychiatric disorders".

"The race will now focus on identification of the key neurodevelopmental genes that underpin these disabling conditions," he added.

Schizophrenia is a chronic, severe, and disabling brain disorder that affects about 1 in 100 people and usually starts in late adolescence or early adulthood. People with schizophrenia experience persistent delusions and hallucinations for instance hearing voices other people don't hear or believing others are reading their minds, controlling their thoughts, or plotting to hurt them.

Bipolar disorder, also known as manic-depressive illness, is a brain disorder that causes unusual shifts in mood, energy, activity levels, and the ability to carry out day-to-day tasks. The symptoms are severe and very different from the normal ups and downs that everyone goes through from time to time.

"Common polygenic variation contributes to risk of schizophrenia and bipolar disorder."
Shaun M. Purcell, Naomi R. Wray, Jennifer L. Stone, Peter M. Visscher, Michael C. O'Donovan, Patrick F. Sullivan, Pamela Sklar and other members of the The International Schizophrenia Consortium.
Nature Advance online publication 1 July 2009.
DOI:10.1038/nature08185

Source: Massachusetts General Hospital, NIMH.

: Catharine Paddock, PhD

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