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Study Finds Wide Range of Rare Mutations Linked to Schizophrenia

NEW YORK (GenomeWeb News) – Individuals with schizophrenia are more likely to carry rare genetic variants than unaffected individuals — particularly in genes involved in brain development and function, new research indicates.
Research led by teams at the University of Washington, Cold Spring Harbor Laboratory, and the National Institute of Mental Health compared the rate of genetic duplications and deletions in schizophrenic and non-schizophrenic individuals. What they found flies in the face of the once accepted “common disease-common allele” model for schizophrenia. Instead the results, published online today in Science Express, hint that many mutations in many genes could contribute to schizophrenia.
“From that perspective, if nothing else, I’m sure we’ll get some discussion going,” co-lead author Jon McClellan, a child and adolescent psychiatrist at the University of Washington, told GenomeWeb Daily News.
About one percent of the population has schizophrenia, a psychiatric condition characterized by hallucinations, delusions, and disordered thinking that usually manifests itself in during late adolescence or early adulthood. Although environmental factors influence it, there is strong evidence that complex genetics contribute to schizophrenia.
As with many common diseases, researchers once viewed schizophrenia as a condition that was caused by a set of shared mutations: the common disease-common allele idea. But recent research suggests that there may be hundreds or even thousands of different mutations that cause this and other complex genetic diseases, McClellan explained.
Similarly, work published in Science last year — by many of the same investigators involved in this study — indicated that autism spectrum disorders are often associated with a variety of new deletions and duplications.
For the latest paper, the team compared genomic DNA from 150 schizophrenic adults with 268 ancestry-matched controls, looking for structural variants larger than 100 kilobases using ROMA 85K probe microarrays. They then validated and refined these results using Illumina 550K microarrays and NimbleGen 2.1M-feature HD2 microarrays.
Though there were not differences in the rate of common mutations, rare or novel mutations were more than three times as common in those with schizophrenia than in non-schizophrenic subjects. Roughly 15 percent of schizophrenic adults had duplications or deletions, compared to about five percent of control individuals. Among those who developed schizophrenia when they were 18-years-old or younger, that number was even higher — up to 20 percent.
In an independent experiment, NIMH researchers compared those with childhood onset schizophrenia — diagnosed before 12 years of age — with their parents. Using genome-wide scans done with Affymetrix 500K SNP Arrays, Agilent 185K or 244K ArrayCGH, and custom BAC arrays, they found that 28 percent of individuals with childhood onset schizophrenia had rare mutations, compared to 13 percent of controls. Most of these appear to have been inherited from unaffected parents.
“If severe mutations leading to schizophrenia are individually rare, then each individual mutation will explain only a small number of patients, or even only one patient,” the authors wrote. “Virtually every rare structural mutation detected in our original series was different.”
This suggests that researchers need to focus on genes within commonly affected pathways rather than on specific alleles, McClellan said.
Intriguingly, many of the mutations detected in both arms of the study affected genes involved in neurobiological pathways — particularly those involved in brain development and communication. Others were in genes previously linked to schizophrenia or autism.
Still, it’s too early to say which of genes, if any, are involved in schizophrenia. To get to the bottom of that, McClellan suggested, the best bet is selecting a suspect gene and sequencing it in a group of schizophrenic individuals to see if they also have distinct mutations in that gene. “If you find lots of other mutations in that gene then it suddenly gets a lot more interesting,” he said.
Not everyone is optimistic about the way schizophrenia genetics are shaking out. Some clinicians are discouraged by the idea that so many unique mutations might be behind one condition, McClellan said: “Sometimes this demoralizes people.” But complex genetics don’t necessarily mean it will be more difficult to develop new therapeutics, he added, especially if researchers start to piece together affected genetic pathways.

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