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 rs3131296 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 — rs12807809 in the NRGN gene on chromosome 11 and rs9960767 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 rs12807809 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 rs9960767 increased the odds of schizophrenia by 1.23 times.

(23andMe customers can check their data for all SNPs mentioned in this post by clicking on the “rs” numbers, which are linked to the Browse Raw Data feature.)

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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Biomedical research conducted in the last decade has impressed upon society that mental illnesses such as schizophrenia, alcohol dependence and major depression can have genetic bases. Unfortunately, the public’s scientific knowledge has not necessarily translated into social acceptance.

“The landscape surrounding mental illness has changed a great deal over the last decade. Support for medical treatment has grown, but tolerance for the mentally ill … remains low.”

University of Pennsylvania sociologist Jason Schnittker came to that conclusion after comparing the results of nationwide surveys given in 1996 and 2006, looking at the data provided by 1,400 respondents in each case on the public perception of mentally ill people.

His work was published online earlier this month in the journal Social Science and Medicine.

The General Social Survey tracks social and demographic trends and is conducted every other year. Schnittker chose to study the results of the mental health sections of the survey only.

The respondents were presented with three short stories, each involving a person described as having schizophrenia, alcohol dependence or major depression — though the survey did not identify them as such. After reading about the characters, the respondents were asked how likely they thought each person’s mental illness was to be caused by reasons ranging from environmental factors such as stress, to a genetic problem, to God’s will.

The results suggest that genetic associations for these conditions lead to increased support for medical treatments, but have little positive effect on respondents’ tolerance for the mentally ill.

For example, Schnittker found respondents strongly supported medical treatment for the character with schizophrenia, even to the point of legally requiring it, in part because their increased understanding of the illness as genetically based was correlated with their perception of schizophrenics as dangerous. On the other hand, survey respondents did react react somewhat more favorably toward the character with depression in 2006 compared to 1996, and were more socially accepting.

“In this case,” Schnittker wrote, “depression is no longer seen as a sign of personal weakness, but rather is seen as a disease to be nurtured, treated and perhaps accepted as natural.”

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Even as the genetic studies on schizophrenia released this week illustrate our progress toward the ultimate goal of personalized medicine, they also bring to mind the challenges that still lie ahead.

All three studies focus on identifying the genetic bases of schizophrenia, a mental disorder characterized by hallucinations, delusions and the decreased ability to plan and organize. These symptoms typically manifest during a patient’s late teens or early 20s.

One study led by Cardiff University researcher Michael O’Donovan identified single nucleotide gene variants (SNPs) associated with schizophrenia. As detailed in the journal Nature Genetics, the researchers started with 12 variants, narrowed the list to six after replicating the tests on several thousand study participants and finally identified three SNPs associated with the disease.

Unfortunately, the variant ultimately found to have the strongest association with schizophrenia — rs1344706 — is not included in 23andMe’s database. Yet the SNP’s effects are so small — it increases the chances of schizophrenia by only about 12 percent among people who have the higher risk version — that it offers limited information.

The other studies — one from the International Schizophrenic Consortium and one from deCODE and the SGENE Consortium — which appear in the journal Nature opted to look for genetic associations by checking copy number variants, DNA segments with deletions or duplications that can be inherited.

One group found three deletions — one on chromosome 1 and two on chromosome 15 — that showed up in a few dozen people out of thousands sampled and were more common among people with schizophrenia. The other group identified two of those three deletions. They also found that people with schizophrenia tend to have more rare copy number variants — both duplications and deletions — in their genomes compared to people without the disease.

“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,” said International Schizophrenic Consortium member and study co-author Pamela Sklar in a statement.

One of the frustrations schizophrenia researchers have encountered is that while the disease is fairly common — affecting one percent of Americans — the genetic basis of schizophrenia has been difficult to pinpoint. One as-yet unsolved mystery is how the disease, which has a high degree of heritability, is as prevalent as it is when correlated with the fact that people who have schizophrenia and other similar mental disorders have fewer offspring.

These studies suggest that very rare gene mutations might play more of a role in the disease than had previously been supposed. That’s valuable information for scientists, and may explain why the genetics of schizophrenia have been so difficult to figure out. But it also suggests that it will take much more research to understand the genetic risk factors underlying schizophrenia than many other diseases.

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A study published online yesterday in Science Express suggests that for schizophrenia at least, and perhaps other mental disorders, that approach might not be the way to go.

Schizophrenia is a debilitating psychiatric disorder that affects approximately one percent of the population. People with schizophrenia suffer from hallucinations, delusions, and disorganized thinking. The illness greatly impacts social and occupational functioning and has enormous public health costs.

The authors of the paper propose that a genetic predisposition to schizophrenia is caused by structural variations in the genome such as deletions, duplications, and re-arrangements of genetic material instead of variation at SNPs. Furthermore, they think that these structural variations might be different for different patients, meaning that it would be difficult to ever find DNA markers that are predictive for the disease.

The researchers used new technologies to look for structural variations in 150 people with schizophrenia or schizoaffective disorder and 268 healthy controls with no history of neurological or psychiatric illness. They found that individuals with schizophrenia were much more likely than controls to have structural variations that affected genes (as opposed to non-coding parts of the genome). The association was strongest in people who developed symptoms while 18 years old or younger.

Virtually every structural variant the researchers detected in the individuals with schizophrenia was unique, though sometimes patients had differing mutations in the same genes. Genes involved in brain development were the most affected.

The results of this study don’t prove that any one gene is associated with schizophrenia, but they do suggest that researchers who want to understand the genetics of this illness, and maybe other complex psychiatric disorders, should perhaps focus their efforts on structural variations instead of SNPs.

That doesn’t mean SNPs aren’t useful. Almost every day we’re learning something new about how subtle single-letter DNA variations between people may affect their health. But some questions won’t be answered until scientists have a better understanding of many other types of genetic variation as well – not to mention the contribution of other factors such as diet, personal habits and environmental exposures.

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