Tuesday, December 23, 2008

Schizophrenia and copy numbers (Paternal Age)

Schizophrenia and copy numbers
Copy number variations are much more frequent in people with schizophrenia.
Staff Writers 31/03/2008 12:11:20 Source: Cold Spring Harbor Laboratory

Using a new method that can be applied in the study of other psychiatric illnesses, scientists have identified multiple, individually rare gene mutations in people with schizophrenia that may help explain how that devastating illness is caused.

The team, from Cold Spring Harbor Laboratory (CSHL) in the US, the University of Washington and the US National Institute of Mental Health, screened for copy number variations, or CNVs, in the genome.

They found that deletions, disruptions and duplications of normal genes, most of them rare, were three to four times more frequent in people with schizophrenia than in controls.

The researchers used a novel method to study their two-cohort sample, which included 418 individuals, 150 of whom had schizophrenia or schizoaffective disorder. Instead of trying to show a statistical correspondence between a large group of people with schizophrenia and irregularities in common versions of genes, the team began by looking for "glitches" or changes in DNA that are likely to disrupt gene function.

Then they compared which genes -- with what kinds of functions -- were impaired, both in the healthy subjects and those with schizophrenia.

The results were striking. Rare mutations showed up in only five per cent of the healthy controls versus 15 per cent of those with schizophrenia. The rate of rare mutation was higher still -- 20 per cent -- among an early-onset subset of patients, who had developed schizophrenia before age 19.

"This part of our findings indicates something we didn't know before: that rare structural mutations in genes, while present in both healthy people and people with schizophrenia, are much more likely to occur among people with the illness," lead author Assistant Professor Jonathan Sebat from CSHL, said.

"This suggests a previously unknown role for rare mutations in the causation of schizophrenia."

The second part of the research aimed to answer a key question about the genes discovered to be irregular: what were their functions? Were their functions similar or different in healthy people versus those with schizophrenia?

Here, too, the results were striking. "In people with schizophrenia, almost half the time the disrupted genes were involved in pathways important in brain development," Sebat said. "By contrast, when we looked at the set of genes that were disrupted in healthy people, we found that they were not overrepresented in any particular pathway."

In an online paper in Science (DOI: 10.1126/science.1155174), the team noted that of 24 rare mutations seen in the schizophrenia group, 11, or 45 per cent, affect cellular signalling pathways critical to neuronal cell growth, migration, proliferation, differentiation, apoptosis and synapse formation.

Some of the affected pathways have turned up in past studies of schizophrenia, notably those involving signalling in neuregulin, a growth factor, and glutamate, a neurotransmitter.

While the study, as the scientists directly concede in their paper, "does not prove the involvement with the illness of any specific variant, or even the involvement of any specific gene," it does, however, indicate a role for rare mutations that disrupt genes in pathways of neuronal development and regulation.

The results are powerful because they link specific structural variation in genes with specific functions known to be important in the early years of life, during which schizophrenia develops in many patients.

This important result leads the scientists to advocate broad use of the method they employed in the study. Gene discovery in complex psychiatric illnesses "should focus on methods that allow detection of structural mutations" across the genome in affected individuals, the team urges.

"Although each mutation discovered may be individually rare, collectively the total number of disease-causing variants in a gene [found to be] relevant to the disorder may explain a substantial number of cases."

Sebat is currently applying the mutation-screening method in studies involving a greater number of patients and in other illnesses. Among other things, he is seeking to determine whether spontaneous mutations play as significant a role in schizophrenia as they do in autism, as revealed by a study he co-authored a year ago with CSHL Professor Michael Wigler.

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