Published online 30 July 2008 | Nature | doi:10.1038/news.2008.994

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Gene surveys identify schizophrenia triggers

Genome deletions raise chances of developing mental illness.

Rare genetic changes associated with a heightened risk of schizophrenia have been revealed by two independent studies.

The surveys have identified sections of the human genome that, when deleted, can elevate the risk of developing schizophrenia by up to 15 times compared with the general population.

DNAGenome deletions can raise the risk of schizophrenia.Getty

Schizophrenia is a serious mental health problem and affects around 1 in every 100 people at some point during their lives. Genetic factors are thought to account for more than 70% of cases. But unlike many diseases with a genetic basis — and in common with many other psychiatric disorders — researchers have struggled to locate genes linked to the occurrence of the disease.

The new findings come from two large-scale studies done by multi-national collaborations, both of which are published in Nature this week. The first study comes from the International Schizophrenia Consortium (ISC)1, a collaboration of researchers from 12 institutions in Europe, the United States and Australia; the second comes from the SGENE consortium2, made up of 18 institutions across Europe, the United States and China.

Genome trawl

The ISC team studied the genomes of 3,391 patients with schizophrenia, looking for a specific type of genetic error called a copy number variation, in which a section of the genome has been deleted or duplicated.

The SGENE collaboration took a slightly different approach by cataloguing all the copy number variations between 15,000 parents and their children. They then looked for matches to these variations in two sets of schizophrenia patients numbering 1,433 and 3,285.

Both groups report genetic deletions associated with schizophrenia in the same three locations, on chromosomes 1 and 15, along with a third deletion on chromosome 22 that has previously been connected with increased susceptibility to schizophrenia. The SGENE collaboration located an additional deletion on chromosome 15, whereas the ISC found that people with the disease are generally more likely to carry rare chromosomal structure changes than those without the disease.

Although these deletions confer a greatly increased risk of schizophrenia (estimated to be between 3 and 15 times greater for different deletions), each occurs only rarely in the population. The frequency of these deletions in the population at large is not yet clear, but is believed to be around 1%.

Because the variations are so rare, large collaborative studies are probably the best way to make headway on understanding the genetic basis of schizophrenia and similar psychiatric disorders. “We may have to identify a larger number of rare but high-risk variants to understand the genetic contribution to susceptibility,” says Kári Stefánsson, chief executive of deCODE genetics — a member of the SGENE collaboration.

Promising leads

Although these deletions do not offer a complete explanation of the genetic basis of schizophrenia, the replication of the findings between the two studies is important. “The fact that there are two independent studies that come at the problem from different angles and using different methodologies is fantastic for psychiatric genetics,” says Pamela Sklar of Harvard Medical School in Cambridge, Massachusetts, part of the ISC study.

Jonathan Flint, who studies the genetic basis of psychiatric diseases at the Wellcome Trust Centre for Human Genetics at the University of Oxford, UK, agrees that the results are a major advance, but points out that converting this association into a better understanding of the biology of schizophrenia is far from trivial. The genetic changes on chromosome 22 have been known for some time, he says, but the exact genes that cause the increase in risk still remain unclear.

Nevertheless, these are the first deletions associated with schizophrenia to be identified in such a large sample and across several populations, Stefánsson adds. “Schizophrenia is a disorder affecting thoughts and emotions. It is therefore a quintessentially human disease, but one that is little understood biologically and which is difficult to diagnose. These findings are important because they shed light on its causes and provide a first component to a molecular test to aid in clinical diagnosis and intervention.”

"It is very important to find out who is at risk [of schizophrenia] so they can avoid triggers such as cannabis," says Marjorie Wallace, chief executive of the UK mental-health charity SANE. "But over the years we have seen many false positives in the search for the gene or genes, and we would therefore treat these findings with some caution. Although encouraging, they are a long way from finding the causes, treatment and, above all, much needed prevention of psychotic illness."

A further study, published in Nature Genetics this week3, reports an association between a different genetic variation, called a single nucleotide polymorphism, in which a single DNA base has been changed, and a rise in the risk of schizophrenia. Michael O'Donovan of Cardiff University, UK, and his colleagues found that the probable schizophrenia susceptibility gene is ZNF804A, which the authors suspect regulates gene expression. Unlike the other studies, this type of variants is common but confers only a small increase in risk. 

For more on what these rare deletions can tell us about the genetics of schizophrenia, listen to Kari Stefansson, CEO and founder of deCODE genetics, on this week's Nature Podcast.

  • References

    1. The International Schizophrenia Consortium, Nature Advance online publication doi:10.1038/nature07239 (2008).
    2. Stefansson H. et al. Nature Advance online publication doi:10.1038/nature07229 (2008).
    3. O'Donovan, M. et al. Nature Genet. Advance online publication doi:10.1038/ng.201 (2008).
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