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Study Links Elevated De Novo CNV Rate to Bipolar Disorder

NEW YORK (GenomeWeb News) – De novo copy number changes are more common in individuals with bipolar disorder than those without, a new study suggests.

Researchers from the US, Germany, and Ireland used array comparative genomic hybridization to look at the prevalence of de novo copy number changes in the genomes of 185 individuals with bipolar disorder and their parents, another 177 parent-child trios in which the child was diagnosed with schizophrenia, and 426 unaffected control trios.

The findings, reported in an online study in Neuron today, suggest that rare CNVs spring up more often in individuals with bipolar disorder than in those without. That pattern was particularly pronounced in individuals who got bipolar disease before turning 18 years old. As reported in past studies, the team also saw an over-representation of the rare, de novo copy number alterations in individuals with schizophrenia relative to the control group.

"Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases," senior author Jonathan Sebat, a psychiatry and psychiatric disease researcher at the University of California at San Diego who is also affiliated with the center's Institute for Genomic Medicine, and colleagues wrote.

While bipolar disorder is thought to be quite highly heritable, previous studies suggest that the genetic contributors to this mood disorder are complex and variable, the researchers explained. And because studies focused on common genetic variants have unearthed only a few suspicious genes, they decided to focus on rarer variants for the new study — specifically, de novo CNVs, copy number changes in a child's genome that are not found in either parent.

"We reasoned that if rare highly penetrant CNVs contribute to risk for bipolar disorder, the genetic effect would be most evident for de novo mutations," the study authors wrote.

To test this notion, researchers used array CGH to assess CNV patterns in individuals from 788 parent-child trios using the NimbleGen HD2 platform. Children in 185 of the trios had been diagnosed with bipolar disorder and 177 had schizophrenia, a condition already linked to an uptick in de novo CNVs.

"While the primary disease focus of this study was [bipolar disorder], the inclusion of an additional schizophrenia cohort served first to replicate the one previous study of de novo CNVs in [schizophrenia]," Sebat and co-authors noted, "and second to enable a valid comparison of patterns of de novo CNVs in [bipolar disorder] with another disorder."

Along with the unaffected control group, comprised of 426 unaffected parent-child trios, the team also assessed 45 children with autism spectrum disorder who had been tested before, along with their parents. Three of the children with ASD had previously been shown to carry de novo CNVs.

After the initial array CGH analyses and validation testing using Oxford Gene Technology custom tiling-resolution CGH arrays, the researchers were left with almost two dozen de novo CNVs in the trios: nine de novo duplications and 14 de novo deletions.

Specifically, the team found 10 de novo CNVs in eight of the 188 individuals from the bipolar disorder group. Another nine de novo CNVs were found in eight of the 177 individuals with schizophrenia who were tested.

The rate of de novo CNVs was much lower in the control group, where researchers saw four CNVs in the genomes of four of 426 individuals tested.

The team's analyses suggest that de novo CNVs are also more common in individuals with bipolar disorder who were younger than 18 years old at the age of onset.

Analyses of the new CNVs data also hinted that large, inherited duplications may be a bit more common in families affected by bipolar disorder, though those involved in the study cautioned that larger sample sizes are needed to determine if and how inherited CNVs contribute to bipolar risk. Likewise, they noted, additional studies should offer a clearer picture of the risk associated with de novo copy number changes.

"High-throughput sequencing in a much larger number of trios will be needed to determine the total contribution of de novo mutation to risk for [bipolar disorder] and [schizophrenia] in the population," study authors concluded.

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