Jul 3, 2009 - Research

Researchers Show Importance Of Common DNA Variants In Schizophrenia


Schizophrenia, a devastating mental illness that affects about one out of every 100 people, is known to have a large genetic component. But scientists have had little luck in finding genes that are responsible for large numbers of cases.   This in turn has hindered the search for new treatments that could provide relief to the tens of millions of schizophrenics worldwide.

But now new research has identified several common DNA variants that can influence the risk of developing schizophrenia. The key to this new success was data sharing – three large consortia combined their data to enable analysis of almost 13,000 people with schizophrenia and more than 34,000 controls.

All three research groups (SGENE, International Schizophrenia Consortium and the Molecular Genetics of Schizophrenia group) found that variants in a region of DNA that harbors multiple immune-related genes are strongly associated with schizophrenia.   Their results, published this week in Nature, fit with previous data suggesting that there is an autoimmune component to the disease.   These ideas stemmed from data showing that schizophrenics are more likely to be born in the winter or spring, the height of flu season.

As an example of one of these immune region variants, the SGENE analysis found that each C at increased the odds of schizophrenia by 1.19 times compared to someone with two Ts at this SNP.

The SGENE researchers associated two other variants with schizophrenia – in the NRGN gene on chromosome 11 and in the TCF4 gene on chromosome 18 –  that are known to be involved in brain development and cognition. These findings may open up avenues into research for new treatments able to address problems with decision-making and memory in ways that current schizophrenia medications do not.

The NRGN is expressed exclusively in the brain where it plays an important role in chemical pathways related to memory. Each copy of the more common T version of increased the odds of schizophrenia by 1.15 times compared to two copies of the C version.

The protein encoded by the TCF4 gene is essential for normal brain development.   Mutations in this gene have been associated with several disorders characterized by mental retardation.   Each copy of the C version of increased the odds of schizophrenia by 1.23 times.

Last year, several studies suggesting that rare insertions and deletions in the DNA were common in schizophrenia cast doubt on whether genomewide association studies would ever identify common genetic variants associated with the disease. But the results of the International Schizophrenia Consortium show that there are in fact thousands of common variants that show at least some association with schizophrenia.   The authors say that although the effect of each individual variant is small, together they account for at least a third of the disease risk.

“Our results do not exclude important contributions of rare variants for schizophrenia,” the authors write. But their results do show that sequencing and studies of insertions and deletions cannot be the only methods used to study the genetics of schizophrenia. Further genomewide association studies of common variations will also need to be undertaken.

The International Schizophrenia Consortium analysis also found that many of the variations associated with schizophrenia are also associated with bipolar disorder, a finding at odds with the traditional view of psychiatrists that the two are distinct diseases.

“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,” said Dr. Thomas Insel, director of the National Institute of Mental Health, in a statement.

“Of course the big question then is how some people develop schizophrenia and others develop bipolar.”

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