New research led by University of California, San Diego (UCSD) School of Medicine, finds that rare copy number variants (CNVs) where sections of DNA are either duplicated or missing, seem to play a key role in the risk for early onset bipolar disorder, which appears in childhood or early adulthood. The researchers write about their findings in a paper published online on 22 December in the journal Neuron.

CNVs are a particular type of mutation or alteration in the genome where cells end up with an abnormal number of copies of sections of DNA code: either too few, due to deletion, or too many, due to duplication. CNVs can be inherited, or de novo, the latter spontaneously occuring either in the sperm or unfertilized egg, or even in the egg after it has been fertilized.

Previous studies have already established that rare CNVs contribute to risk for some some neuropsychiatric disorders such as schizophrenia and autism, but the role they play in bipolar disorder, formerly known as manic depression, has been less clear.

Nobody knows what causes bipolar disorder, although we know there is a clear genetic contribution, since the disorder runs in families. But previous studies that have focused primarily on inherited variants have not been very successful at identifying key genes.

In this latest paper, senior investigator Dr Jonathan Sebat, assistant professor of psychiatry and cellular and molecular medicine at UCSD’s Institute of Genomic Medicine, and colleagues, describe how they found de novo CNVs contribute significant genetic risk in about 5% of early onset bipolar disorder.

First author Dheeraj Malhotra, an assistant project scientist in Sebat’s lab, said in other words, the study shows that “having a de novo mutation increases the chances of having an earlier onset of disease”.

While such a result is not enough to point conclusively to a specific gene or region of the genome, they lend strong support to the idea that rare CNVs contribute to the development of early onset bipolar disorder, said Malhotra. He explained you would have to sequence whole genomes from a large number of families with bipolar disorder before you could identify all the de novo CNVs that might be involved.

For the study, the researchers performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios (parents and offspring). 185 of the offspring were diagnosed with bipolar disorder, 177 with schizophrenia, and 426 were healthy controls.

The analysis showed that de novo CNVs occured at a signficantly higher frequency in participants with bipolar disorder compared with controls and were particularly enriched among those where onset occurred at younger than 18 years.

The results also showed significant enrichment of de novo CNVs in those with schizophrenia, confirming findings from previous studies.

The researchers conclude:

“Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.”

Funding for the study came from a number of sources, including: the National Institutes of Health, Ted and Vada Stanley, the Beyster family foundation, Wellcome Trust, Science Foundation Ireland, the Sidney R. Baer, Jr. Foundation and the Essel Foundation.

Written by Catharine Paddock PhD