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Exome Sequences Reveal Role for De Novo Mutations in Schizophrenia

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Individuals with sporadic schizophrenia tend to carry more new, potentially deleterious, genetic changes than individuals in the general population, according to an exome sequencing study of schizophrenia-affected families that appeared online in Nature Genetics yesterday.

"The occurrence of de novo mutations, as observed in this study, may in part explain the high worldwide incidence of schizophrenia," co-senior author Guy Rouleau, a researcher at the University of Montreal and director of its CHU Sainte-Justine Research Center, said in a statement.

Researchers from Canada and France did exome sequencing on individuals from 14 parent-child trios, each comprised of an individual with schizophrenia and his or her unaffected parents. In the process, they found 15 de novo mutations in coding sequences from eight individuals with the psychiatric condition, including four nonsense mutations predicted to abbreviate protein sequences.

"Our study supports the notion that [de novo mutations] may account for some of the heritability reported for schizophrenia," Rouleau and his co-authors wrote, "while providing a list of genes possibly involved in disease pathogenesis."

Recent exome sequencing studies involving parent-child trios have implicated de novo mutations in other brain-related conditions, including autism spectrum disorder and mental retardation.

For the current study, researchers used this approach to look at schizophrenia, a psychiatric condition with a range of symptoms and severity that's thought to have complex genetic underpinnings.

After isolating DNA from blood samples taken from individuals in 14 parent-child trios, the team used Agilent SureSelect Human All Exome kits to capture coding sequences that were subsequently sequenced with the Illumina GAIIx.

The families included in the study each had an affected child but no other close relatives with a history of schizophrenia or other conditions characterized by psychoses.

To detect de novo genetic changes specific to schizophrenia, the team compared coding sequences from affected individuals with the human reference genome, with both of his or her parents, and with 26 unrelated control individuals.

Using this approach, researchers found 73 potential de novo mutations, 15 of which were verified by Sanger sequencing. Of these, 11 were missense mutations predicted to alter the amino acid sequence of the resulting protein and four were nonsense mutations predicted to truncate it.

Among the genes containing nonsense mutations were the zinc finger protein-coding gene ZNF480, the karyopherin alpha 1 gene KPNA1, the low-density lipoprotein receptor-related gene LRP1, and the ALS-like protein-coding gene ALS2CL.

The 15 mutations were found in coding sequences from eight of the individuals with schizophrenia, hinting at a higher de novo mutation rate in individuals with sporadic schizophrenia than is predicted in the population overall.

This difference seems to be specific to exomes, researchers reported, noting that de novo mutation rates across the entire genome are likely comparable in those with or without schizophrenia.

"Our study strongly suggests that the enrichment of [de novo mutations] within the coding sequence of individuals with schizophrenia may underlie the pathogenesis of a substantial number of these individuals," they wrote.

By looking at the genes affected by these mutations and the consequences of the genetic changes, researchers say, it may be possible to learn more about brain development and function, in general, and about some of the biological processes that are altered in schizophrenia specifically.

"Because the mutations are located in many different genes, we can now start to establish genetic networks that would define how these gene mutations predispose to schizophrenia," first author Simon Girard, a University of Montreal graduate student, said in a statement. "Most of the genes identified in this study have not been previously linked to schizophrenia, thereby providing new potential therapeutic targets."

Down the road, some of the genes identified in the study may also prove useful in schizophrenia screening, researchers noted, though they conceded that more research is needed to see how findings from the current study relate to other schizophrenia cases.

"Although sporadic cases are not necessarily representative of all individuals with schizophrenia," they concluded, "these new candidates should be further investigated as potentially implicated in this disease."