Findings from a 2-pronged approach add to evidence of shared genetic susceptibility across major psychiatric disorders.
A new study suggests there may be an overlap between rare genetic variations linked to bipolar disorder (BD) and those implicated in schizophrenia and autism.
The study, by researchers at the University of Iowa Carver College of Medicine, Johns Hopkins School of Medicine, and Cold Spring Harbor Laboratory and published recently in JAMA Psychiatry, adds to the growing understanding that many psychiatric diseases share genetic roots, but is among the first to suggest a genetic overlap between bipolar disorder and autism.
Bipolar disorder is one of the most important psychiatric illnesses because it is fairly common – affecting between 1 and 3 percent of the population – and quite debilitating. Although many patients are helped by treatments, such as lithium, about one third of people affected by BD do not do well with current therapies. Although it’s long been 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 uncover several so-called common variations, but none of these variations alone have a large effect. Even more recently, the advent 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, MD, UI 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.”
Potash and his colleagues devised a two-pronged strategy, combining a case-control approach with family-based exome sequencing to maximize their chances of identifying rare variants that contribute to BD.
The idea behind the case-control approach is simple: 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. Very large datasets are key to the success of this approach.
Exome sequencing of families affected by a disease is more sophisticated. Comparing exome sequences of related individuals, affected and unaffected by BD, can 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.
Overall the family study identified 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. The team then 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.
Despite the relatively large size of the combined datasets, the approach was not powerful enough to identify any of the individual rare variants as definitively associated with BD. However, 19 genes stood 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,” says Potash, who also is the Paul W. Penningroth Professor and Chair of Psychiatry and a member of the Pappajohn Biomedical Institute at the UI.
However, when the team considered 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 says. “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 adds. “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.
In addition to Potash, the research group also included senior authors Peter Zandi at Johns Hopkins School of Medicine, and Richard McCombie at Cold Spring Harbor Laboratory, and lead study author Fernando Goes, at Johns Hopkins School of Medicine. Additional UI co-authors of the study were Virginia Willour and Eric Monson.
Funding: The research was funded by grants from The National Institute of Mental Health at the National Institutes of Health (NIH) and the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD).
Source: Jennifer Brown – University of Iowa Health Care
Image Credit: The image is in the public domain.
Original Research: Abstract for “Exome Sequencing of Familial Bipolar Disorder” by Fernando S. Goes, MD; Mehdi Pirooznia, MD, PhD; Jennifer S. Parla, PhD; Melissa Kramer, BS; Elena Ghiban, BA; Senem Mavruk, BA2 Yun-Ching Chen, PhD; Eric T. Monson, BS; Virginia L. Willour, PhD; Rachel Karchin, PhD; Matthew Flickinger, PhD; Adam E. Locke, PhD; Shawn E. Levy, PhD; Laura J. Scott, PhD; Michael Boehnke, PhD6; Eli Stahl, PhD8,9; Jennifer L. Moran, PhD10; Christina M. Hultman, PhD; Mikael Landén, MD; Shaun M. Purcell, PhD; Pamela Sklar, MD, PhD; Peter P. Zandi, PhD; W. Richard McCombie, PhD; and James B. Potash, MD, MPH in JAMA Psychiatry. Published online April 27 2016 doi:10.1001/jamapsychiatry.2016.025
Exome Sequencing of Familial Bipolar Disorder
Importance Complex disorders, such as bipolar disorder (BD), likely result from the influence of both common and rare susceptibility alleles. While common variation has been widely studied, rare variant discovery has only recently become feasible with next-generation sequencing.
Objective To utilize a combined family-based and case-control approach to exome sequencing in BD using multiplex families as an initial discovery strategy, followed by association testing in a large case-control meta-analysis.
Design, Setting, and Participants We performed exome sequencing of 36 affected members with BD from 8 multiplex families and tested rare, segregating variants in 3 independent case-control samples consisting of 3541 BD cases and 4774 controls.
Main Outcomes and Measures We used penalized logistic regression and 1-sided gene-burden analyses to test for association of rare, segregating damaging variants with BD. Permutation-based analyses were performed to test for overall enrichment with previously identified gene sets.
Results We found 84 rare (frequency <1%), segregating variants that were bioinformatically predicted to be damaging. These variants were found in 82 genes that were enriched for gene sets previously identified in de novo studies of autism (19 observed vs. 10.9 expected, P = .0066) and schizophrenia (11 observed vs. 5.1 expected, P = .0062) and for targets of the fragile X mental retardation protein (FMRP) pathway (10 observed vs. 4.4 expected, P = .0076). The case-control meta-analyses yielded 19 genes that were nominally associated with BD based either on individual variants or a gene-burden approach. Although no gene was individually significant after correction for multiple testing, this group of genes continued to show evidence for significant enrichment of de novo autism genes (6 observed vs. 2.6 expected, P = .028).
Conclusions and Relevance Our results are consistent with the presence of prominent locus and allelic heterogeneity in BD and suggest that very large samples will be required to definitively identify individual rare variants or genes conferring risk for this disorder. However, we also identify significant associations with gene sets composed of previously discovered de novo variants in autism and schizophrenia, as well as targets of the FRMP pathway, providing preliminary support for the overlap of potential autism and schizophrenia risk genes with rare, segregating variants in families with BD.
“Exome Sequencing of Familial Bipolar Disorder” by Fernando S. Goes, MD; Mehdi Pirooznia, MD, PhD; Jennifer S. Parla, PhD; Melissa Kramer, BS; Elena Ghiban, BA; Senem Mavruk, BA2 Yun-Ching Chen, PhD; Eric T. Monson, BS; Virginia L. Willour, PhD; Rachel Karchin, PhD; Matthew Flickinger, PhD; Adam E. Locke, PhD; Shawn E. Levy, PhD; Laura J. Scott, PhD; Michael Boehnke, PhD6; Eli Stahl, PhD8,9; Jennifer L. Moran, PhD10; Christina M. Hultman, PhD; Mikael Landén, MD; Shaun M. Purcell, PhD; Pamela Sklar, MD, PhD; Peter P. Zandi, PhD; W. Richard McCombie, PhD; and James B. Potash, MD, MPH in JAMA Psychiatry. Published online April 27 2016 doi:10.1001/jamapsychiatry.2016.025