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HudsonAlpha, UMich Team to Sequence Thousands of Individuals for Bipolar Disorder Study

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By Andrea Anderson

Researchers at the HudsonAlpha Institute for Biotechnology and the University of Michigan plan to use whole-genome sequencing to look for genetic contributors to bipolar disorder under a $7.8 million award from the National Institute of Mental Health.

Over the next three years, the researchers will sequence the complete genomes of around 1,000 cases and 1,000 controls in an effort to learn more about the biological underpinning of the disease and to find clues about treating it more effectively. While genome-wide association studies have already revealed a few common variants contributing to bipolar disorder, the large-scale sequencing approach is expected to unearth additional SNPs and structural variations involved in the disease, including some that may turn up less frequently in the population.

"With sequencing allowing us to explore a broader range of the allele frequency spectrum for the disease … we can look at less common and rarer variants with sequencing under the hypothesis that such less common or rare variants might be important," Michael Boehnke, one of the study's lead investigators, told Clinical Sequencing News. "The sequencing study will allow us to address that hypothesis in a way that genome-wide association studies really do not."

Boehnke is the director of the University of Michigan Center for Statistical Genetics and also directs the University of Michigan's Genome Science Training Program.

HudsonAlpha President and Director Richard Myers is leading the effort at that institute, where the bulk of the experimental work will take place, while Boehnke will head the University of Michigan arm of the study, which will focus on statistical analyses of the data. Both institutes will likely contribute to the bioinformatics side of the study.

"Our research team combines strengths in high-throughput genetics and genomics and development and application of innovative computational and statistical methods to maximize the benefits of cutting-edge technologies," Myers said in a statement.

At the moment, the bipolar disorder sequencing study primarily involves researchers from HudsonAlpha and University of Michigan, though Boehnke said the effort may ultimately include collaborators and participant samples from other institutions as well.

"To be successful in the genetics of something so difficult as bipolar disorder, something so complex, it's really critically important to build collaborations," he explained, "both within our own study in terms of samples for initial sequencing and follow-up genotyping and sequencing, and also for confirming results or disproving results across other studies."

Bipolar disorder is a chronic mental illness that affects roughly one percent of the population. It's often diagnosed before the age of 25 years old and is characterized by dramatic mood and behavioral changes that oscillate between mania and depression.

The disease seems to have substantial heritability, since individuals with an affected parent or sibling are more likely to develop bipolar disorder than those in the general population.

"There's a strong familial component," Boehnke explained. "It's not necessarily the case that that strong familial component would translate to a genetic basis, but it's entirely possible that it would."

From GWAS to Sequencing

The project is the latest in a history of genetic studies of bipolar disorder. For instance, Boehnke, Myers, and other researchers at the University of Michigan, HudsonAlpha, and elsewhere published a genome-wide association study involving thousands of bipolar disorder cases and controls in the Proceedings of the National Academy of Sciences in 2009. But even though some loci have been linked to bipolar disorder, the overall number of known genetic contributors is still relatively small.

With the availability of sequencing strategies that are more inexpensive and high throughput than those available previously, the HudsonAlpha and University of Michigan team decided to take a genome-wide look at bipolar disorder in an effort to learn more about its etiology and treatment.

"The time seemed right for carrying out a large-scale sequencing study," Boehnke said, especially given what he calls the "incredible drop in sequencing prices, the incredible increase in sequencing throughput."

Along with clues about what causes the disease, those involved in the study hope to unearth information for improving its treatment. And since existing bipolar disorder therapies work well for some individuals but are less effective for others, they are keen to find genetic clues for determining which individuals are more or less likely to respond to these treatments.

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"It's the kind of place where more options for treatments and better tailoring of existing treatments would certainly be of great value," Boehnke said. "Those are the kinds of things we would be most optimistic about as sort of mid- to long-term kinds of successes for a project like this. Understanding the etiology better, that's something we can hope for in the nearer term, perhaps."

For the first stage of the study, the researchers plan to use the Illumina HiSeq 2000 platform to do whole-genome sequencing on 1,000 individuals with bipolar disorder and as many unaffected control individuals.

When the group crafted their grant proposal last year, they planned to sequence each genome to a depth of four times coverage while augmenting this whole-genome sequence data with deep exome sequencing.

That plan has changed substantially, Boenke said, with advances in sequencing technology and a drop in sequencing prices now making it more feasible to look across the genome in a uniform way.

At the moment, the team expects to do whole-genome sequencing to a depth of 15 times coverage for each individual, he explained, though that target may move again as technology continues to improve.

The most recent iteration of the project does not involve an exome-sequencing arm that is independent of the whole-genome sequencing effort, which will now provide much greater sequencing depth than previously anticipated. Even so, the team plans to carefully scrutinize coding sequence generated through the whole-genome effort.

A Common Subtype

The genome-sequencing project will focus on individuals with a common subtype of bipolar disorder known as bipolar disorder I.

"What we're hoping to do by picking that relatively common subtype is to have a relatively more homogeneous group of individuals," Boehnke said.

"Whether that clinical greater degree of homogeneity will translate to a genetic greater degree of homogeneity, that's open to question," he added, "but it seems plausible that that would be the case."

Samples for the project will include some bipolar I cases enrolled through the previous GWAS. The researchers also plan to assess some cases and controls from the NIMH repository, along with samples from individuals enrolled through the University of Michigan Depression Center's Heinz C. Prechter repository and studies led by GlaxoSmithKline.

While investigators at HudsonAlpha sequence the samples, collaborators at the University of Michigan will be working in parallel to come up with statistical methods and bioinformatics approaches to analyze the data.

The University of Michigan team includes several members who have tackled similar statistical problems in the past, including Goncalo Abecasis and others involved with developing statistical methods for efforts such as the 1000 Genomes Project and large studies of type 2 diabetes.

"The methods that we develop in these projects, we have every reason to hope and expect, based on past experience, that they'll be used by other groups as well," Boehnke said.

For future phases of the project, the team plans to do comparative studies to determine whether genetic glitches implicated in the discovery phase are present in more than 5,000 other individuals in a study validation group.

These follow-up studies may involve genotyping specific variants in some instances and, in other cases, sequencing genes that contain multiple variants that are each less common or rare, Boehnke said.

Even further down the road, the researchers hope to do additional analyses of the genomes as well, including studies aimed at identifying epigenetic patterns that coincide with bipolar disorder.

"That's one of the places where we would be absolutely hoping to expand the project as sequencing prices continue to go down," Boehnke said. "Rick [Myers] and his team certainly have the expertise to do the relevant sequencing and our group certainly has the expertise to analyze those sorts of data."


Have topics you'd like to see covered in Clinical Sequencing News? Contact the editor at anderson [at] genomeweb [.] com.

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