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Exome Sequencing Study Explores Burden of De Novo Gene Mutations in Schizophrenia

NEW YORK (GenomeWeb News) – Elevated schizophrenia risk appears to stem from a preponderance of deleterious de novo mutations, including recurrent mutations to a handful of potential risk genes, according to an exome sequencing study appearing online today in Nature Genetics.

Columbia University researchers did exome sequencing on nearly 800 individuals with or without schizophrenia, including more than 200 South African and American trios comprised of affected individuals and their parents.

Within coding sequences from individuals with the psychiatric condition, investigators saw an over-representation of spontaneous, potentially deleterious mutations not present in the exomes of either of their parents. And a subset of genes affected by those changes is believed to have roles in early brain development, the team reported, as evidenced by enhanced expression of the genes in the prenatal brain.

"Our findings implicate contribution from a diverse set of de novo mutations to the genomic architecture of schizophrenia," co-senior authors Maria Karayiorgou and Joseph Gogos, both at Columbia University, and their co-authors wrote.

Together with de novo copy number variations, they estimated that de novo coding sequence mutations could be a factor in roughly one-quarter to one-third of sporadic schizophrenia cases.

While the de novo alterations identified in the current study fell across many genes in the sequences tested, four genes proved to be particularly prone to mutations in the schizophrenia group: LAMA2, DPYD, TRRAP, and VPS39. A few more genes with de novo mutations in the schizophrenic group were found to have de novo copy number changes in other individuals with the condition.

In an effort to identify genetic risk factors for schizophrenia, Karayiorgou, Gogos, and their colleagues did exome sequencing on 795 individuals, using DNA extracted from blood samples.

To track down de novo mutations — those that turn up in a child but are not present in either parent — the researchers generated exome sequences for affected and unaffected individuals as well as their parents. These included 231 Afrikaner or American trios with a schizophrenia-affected child and almost three-dozen more Afrikaner trios that did not include an affected individual.

After capturing coding sequences from the samples with either Agilent or Roche NimbleGen kits, the team sequenced each individual's exome with the Illumina HiSeq 2000.

Analyses of the sequences suggested that offspring from the schizophrenia trios were more likely to carry de novo point mutations or small insertions and deletions than those from the control trios. That was particularly true for so-called nonsynonymous changes that are expected to alter the amino acid sequence encoded by a given gene in ways that thwart the function of the resulting protein.

When they looked at a set of genes that tended to be affected by such de novo nonsynonymous changes in individuals with schizophrenia, the researchers saw an over-representation of genes that are expressed in parts of the prenatal brain.

Such patterns hint that some stages of brain development may be especially important to schizophrenia risk, perhaps helping to explain why risk of the disease seems to be higher in children whose mothers were exposed to certain infections and environmental factors during pregnancy.

"Our findings provide a mechanism that could explain how prenatal environmental insults during the first and second trimester of pregnancy increase one's risk for schizophrenia," Karayiorgou said in a statement.

Among the genes that were recurrently mutated de novo in the schizophrenia trios, meanwhile, the team found four genes — LAMA2, DPYD, TRRAP, and VPS39 — that contained new mutations in at least two unrelated individuals with schizophrenia.

Five more genes found to have copy number changes in individuals with schizophrenia in the past contained de novo mutations in affected individuals tested for the new study.

From their findings so far, those involved in the study predicted that there are probably at least 850 different loci that contribute to schizophrenia risk. Now, they say, more research is needed to explore the functional consequences of mutations affecting such sites.

"The challenge remains to identify the affected biological processes and neural circuits and to determine how they are affected," they concluded. "Unbiased network-based approach as well as animal and cellular models of recurrent mutations will be invaluable in reaching this goal."

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