The study, which adds to the growing body of evidence that many psychiatric diseases share genetic roots, was conducted by researchers at the University of Iowa Carver College of Medicine, Johns Hopkins School of Medicine and Cold Spring Harbor Laboratory. The findings are the first to show a genetic overlap specifically between bipolar disorder and autism.
Bipolar disorder is a debilitating mental illness that affects between one and three percent of the population. Although many bipolar patients are helped by drug treatments, such as lithium, about one-third of people affected by BD do not respond well to current therapies.
And while it’s well-known that bipolar disorder is highly heritable, identifying specific genetic variants that contribute to the illness has proven difficult.
Within the last decade, advances in human genome studies have helped scientists uncover many common variations, but none of these variations alone have a large effect. Even more recently, the premier of rapid and relatively cheap next-generation gene sequencing technology has provided an opportunity to find rare variations that might individually have a large effect.
“Common variations are thought to each individually have only a tiny impact — for example, increasing a person’s likelihood of getting a disease by 10 to 20 percent,” says James Potash, M.D., University of Iowa professor and DEO of psychiatry, and senior author of the new study.
“The hope with rare variations is that they individually have a much bigger impact, like doubling or quadrupling risk for disease.”
The researchers used a case-control approach with family-based exome sequencing to maximize their chances of identifying rare variants that contribute to BD.
The case-control approach is fairly simple and works in the following way: If a genetic variant is found more often in the group of individuals who have the disease compared to a control group of people without the condition, then the gene variation might be associated with increasing susceptibility to the disease. Having a huge amount of data is key to the success of this approach.
Family exome sequencing is a little more complicated. When scientists compare the exome sequences of family members — both those affected and unaffected by BD — they are able to distinguish variants that “travel with” or segregate with the disease. This approach has long been used to identify gene variants or mutations that are passed from parents to children that cause disease.
The researchers discovered 84 rare variants (in 82 genes) that segregated with BD and that were also predicted to be damaging to the proteins encoded by those genes. Then they tested the likelihood that these rare variations might be involved in causing BD by looking for them in three large case-control datasets that included genome sequences from a total of 3,541 individuals with BD and 4,774 control patients.
While the approach was not powerful enough to identify any of the individual rare variants as definitively associated with BD, 19 genes did stand out as being over-represented in BD cases compared to controls.
“The results were not strong enough for us to say ‘we have pinpointed the genetic culprits.’ But it was strong enough for us to remain interested in these genes as potential contributors to bipolar disorder,” said Potash, who also is the Paul W. Penningroth Professor and Chair of Psychiatry and a member of the Pappajohn Biomedical Institute at the niversity of Iowa.
However, when the researchers looked at the 19 genes as a group, they realized that several were also members of groups of genes that had been implicated in autism and schizophrenia.
“It turned out that the schizophrenia and the autism genes were all more represented among our 82 genes than you would expect by chance,” Potash said. “And when we looked at our whittled down group of 19 genes, the autism genes continued to be unexpectedly prominent among them.
“With studies like this we are finally, after decades of effort, making real progress in nailing down groups of genes and variations in them that play a role in causing bipolar disorder,” Potash said.
“The mechanistic insights we gain from identifying associated genes we hope will point us in the direction of developing new treatments to make a difference for the many people affected by this illness.”
The findings are published in the journal JAMA Psychiatry.
Source: University of Iowa Healthcare