July 8, 2009

Published Date: 03 July 2009

Scientists have unlocked "the secrets of schizophrenia", according to The Independent. The newspaper says that research has identified thousands of tiny genetic variations which together could account for more than one-third of the inherited risk of schizophrenia.
Three international research teams have undertaken these complex and interlinked genetics studies, which have largely consistent findings. The studies have associated a number of gene variants with the risk of schizophrenia. Environmental factors are

likely to also play a part and the variations identified in these three studies will not be responsible for all cases of schizophrenia. Equally, these associations do not mean that it would necessarily be possible to one day prevent the disease in people carrying these variants.

These findings further the understanding of the biology of schizophrenia and will undoubtedly prompt further research into how these gene variants may affect the physiological processes of schizophrenia. It is too soon to say how the findings will affect the diagnosis, prevention or treatment of this complex disorder, which is probably caused by both environmental and genetic factors. It is also likely that other gene variants, which are still to be identified, play a role in the disorder.


Where did the story come from?These news reports are based on three related genome-wide association studies, published in the peer-reviewed medical journal Nature.

The first study was carried out by the International Schizophrenia Consortium, a collection of researchers from the USA, Australia, UK and other European countries. Funding for this research came from a variety of sources. The second study was a genome-wide association study carried out by Jianxin Shi and colleagues from across the USA, UK and Australia, using the Molecular Genetics of Schizophrenia sample. This study was funded by the National Institute of Mental Health and the National Alliance for Research on Schizophrenia and Depression. The third study, the SGENE-plus, was carried out by Hreinn Stefansson and colleagues from a research consortium with members from countries across Europe, the UK, USA and China. This study was funded by EU grants. In a second aspect to this study, the researchers meta-analysed (pooled the results) of the other two studies above.  

What kind of scientific study was this?Schizophrenia is a complex disorder, with both environmental and genetic factors implicated in its development. All three of these studies were genome-wide association (GWA) studies, which look for particular gene sequences (variants) that are associated with a condition.

This is done by comparing the genetics of those with a condition (in this case schizophrenia) with the genetics of people without it (control subjects). In this way, the variants that are more common in people with schizophrenia can be identified. The contribution of the variants to the risk of disease can then be calculated.

These studies were necessarily complex and all three are linked, as the researchers used each other’s populations to confirm the findings of their own genome-wide association studies. It is common practice with genome-wide association studies to verify the results in a separate population of cases and controls.


The International Schizophrenia Consortium study

This first piece of research compared the gene sequences of 3,322 Europeans with schizophrenia with the genetics of 3,587 control subjects without the condition. The researchers undertook modelling to establish what contribution genetic variation made to the participants’ risk of schizophrenia. They also assessed whether the gene variants that they identified were common to the risk of bipolar disorder and some non-psychiatric diseases.


The Molecular Genetics of Schizophrenia (MGS) sample study

This second study was a GWA and meta-analysis. The case-control study aspect was in the MGS European-ancestry sample, which included 2,681 cases of schizophrenia and 2,653 controls, and an African-American sample with 1,286 case and 973 controls. In the meta-analysis aspect of this study, data on 8,008 cases and 19,077 controls were assessed.


The SGENE-plus study

This third study was an analysis of genome-wide associations performed on a sample of 2,663 cases and 13,498 controls from eight European locations. These were England, Finland (Helsinki), Finland (Kuusamo), Germany (Bonn), Germany (Munich), Iceland, Italy and Scotland. The researchers also combined their population with the populations of both studies above to strengthen their study and enable more accurate identification of gene variants.


What were the results of the study?The International Schizophrenia Consortium study

The researchers found that the strongest association with schizophrenia was in a gene that coded for a protein called myosin, found on chromosome 22. The second-strongest association between variants and risk for schizophrenia was in a region of more than 450 gene variants, found across the major histocompatibility complex (MHC) region on chromosome 6p.

The researchers then confirmed some of their results using data on the participants in the other studies. Through their modelling, they concluded that common variation across multiple genes accounts for about one-third of the total increase in schizophrenia risk, although the influence could be much higher than estimated. They say that the many genes implicated in increasing schizophrenia risk also contribute to the risk of bipolar disorder.


The Molecular Genetics of Schizophrenia (MGS) sample study

The researchers did not find significant links with any gene variants in the case-control aspect of the research at the threshold of significance that they were using. They found a difference in the most common gene variants between people with European ancestry and those with African-American ancestry. When they combined the participants in their study with those in the other two studies, they confirmed the findings that gene variants on chromosome 6p were associated with schizophrenia risk.


The SGENE-plus study

The researchers found an association between a particular gene variant on chromosome 6p in the major histocompatibility complex (MHC) region and the risk of schizophrenia. When they added the participants from the other two studies, they found that four other gene variations, including two in the MHC region, were also significantly linked to schizophrenia risk.


What interpretations did the researchers draw from these results?Researchers in the International Schizophrenia Consortium study concluded that their data supports the involvement of many genes in the risk for schizophrenia and that genes may explain about one-third of the heritability of the disorder. The risk of schizophrenia involved thousands of common variants, which each make a very small contribution to the risk.

The findings of this study, and those of the SGENE-plus study, implicate the MHC region in schizophrenia risk. This is consistent with the idea of an immune component to the disease as the MHC region has a role in immunity responses. However, while the authors say that the association with this region supports a role for infection in the causes of schizophrenia, it “does not provide strong evidence”.

The researchers in the MGS study conclud
ed that they have identified a link between common gene variants on chromosome 6p and schizophrenia. They say that their study and the other studies suggest that these variants have small effects on the risk of schizophrenia. Larger samples may be useful to detect and understand the full range of rare and common gene variants that contribute to the risk of schizophrenia.


What does the NHS Knowledge Service make of this study?The genome-wide association studies confirm what is already known about schizophrenia, that it is a complex disorder with complex causes and that individual gene variants play a small part individually in raising the risk. These studies have consistent findings and conclude that there are associations between schizophrenia and a number of gene variants, largely on chromosome 6 in the major histocompatibility region.

There are several important points to bear in mind when interpreting the results and reporting of these three genetics studies:

Schizophrenia is a complex disorder. These three studies identified several gene variants that play a role in the risk of schizophrenia and it is likely that there are more yet to be identified. Our understanding of the biology and physiology behind the disorder may be furthered by the findings here, which will undoubtedly prompt further research. A better understanding of the biology of an illness raises hopes for better diagnosis, prevention and treatment of the disorder. However, these are still some way off. The findings illustrate the complicated nature of the genetic component of schizophrenia. There is a complex inheritance pattern and many genetic and environmental factors play a part. Not all people who have these gene variants will develop schizophrenia.