On the hunt for genetic clues

HudsonAlpha Institute, U of Michigan search for genetic links to bipolar disorder

Lori Lesko
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HUNTSVILLE, Ala.—Touted as the largest genetic study ofbipolar disorder to date, 169 scientists from 11 countries have discovered anew genetic location contributing susceptibility to the disorder, and foundfurther evidence of a genetic link to the mental illness marked by mood swings,mania and depression. These findings were published Sept. 18 in the onlinejournal Nature Genome. 
The scientific article has set the stage for interest in anew three-year study launched by researchers at the Huntsville, Ala.-based HudsonAlphaInstitute of Biotechnology and the University of Michigan. The institutions areteaming up—this time using whole-genome sequencing to look for geneticcontributors to bipolar disorder—thanks to a $7.8 million award from theNational Institute of Mental Health (NIMH). 
"We are embarking on another large study of bipolar disorderwith our colleagues at the University of Michigan, and these data give us hintson genetic variants to examine further with more in-depth technologies,"Richard Myers, director of the HudsonAlpha Institute, stated in a news releasein late August.
Given the complex nature of bipolar disorder and otherpsychiatric conditions, scientists need to examine variation in the genomes oflarge numbers of individuals, and pool the information together, Myers said.
"Bipolar disorder is severely disabling and oftenlife-threatening," Myers stated. "This study, which will continue into 2014,will increase our understanding of bipolar disorder and support identificationof targeted therapies and approaches for treatment."
Bipolar disorder is a chronic mental illness that affectsroughly 1 percent of the population. Often diagnosed before the age of 25,bipolar disorder is characterized by dramatic mood and behavioral changes thatoscillate between mania and depression, according to the NIMH. Symptoms mayseem like separate problems, so diagnoses have been impeded and therapy oftendelayed.
Doctors have suspected for decades that a bipolar disorderis hereditary since individuals with an affected parent or sibling are morelikely to develop bipolar disorder than those in the general population—butthere was no way to prove it.
The NIMH reports that children with a parent or sibling whohas bipolar disorder are four to six times more likely to develop the illness,compared with children who do not have a family history of the disorder. TheNIMH project encompasses information from more than 7,000 individuals toprovide more accurate prediction of risk, Myers said.
Myers' colleague and friend, Michael Boehnke, director ofthe University of Michigan Center for Statistical Genetics Scientists, is oneof the study's lead investigators.
"There's a strong familial component," saysBoehnke, who is also director of the University of Michigan's Genome ScienceTraining Program. "It's not necessarily the case that that strong familialcomponent would translate to a genetic basis, but it's entirely possible thatit would."
The first phase of the NIMH-funded project will includewhole-genome sequencing of 2,000 individuals; half of who have been diagnosedwith bipolar disorder, and half of whom have not been diagnosed with thedisorder. Scientists will look for similarities among those diagnosed withbipolar as compared with the control population. An additional 5,000individuals will be included in comparative studies addressed with separatefunding.
"We are working exclusively with bipolar I, the most severetype (of bipolar disorder)," said Myers. "It is not just a passing(depression). Once this starts, it seems to set in and massively affect peopleas well as their families and people around them."
Analysis on samples previously collected will be one of thelargest sequencing studies in the world, he said.
Myers is leading the effort at the HudsonAlpha Institute,where the bulk of the experimental work will take place, while Boehnke willhead the University of Michigan arm of the study, focusing on statisticalanalyses of the data.
"Our research team combines strengths inhigh-throughput genetics and genomics and development and application ofinnovative computational and statistical methods to maximize the benefits ofcutting-edge technologies," Myers stated.
Boehnke says the bipolar sequencing study may ultimatelyinclude collaborators and participant samples from other institutions.
To be successful in the genetics of something as complex asbipolar disorder, it's important to build collaborations "both within our ownstudy in terms of samples for initial sequencing and follow-up genotyping andsequencing, and also for confirming results or disproving results across otherstudies," Boehnke says.
In 2009, Myers and Boehnke and a host of researchers fromeach institution published a genome-wide association study involving thousandsof bipolar disorder cases and controls in the Proceedings of the National Academy of Sciences. But even thoughsome loci have been linked to bipolar disorder, the overall number of knowngenetic contributors is still relatively small.
Given what he referred to as the "incredible drop insequencing prices, the incredible increase in sequencing throughput, the timeseemed right for a large-scale sequencing study," Boehnke says.
By comparison, Myers said the Human Genome Project—whichfirst sequenced a single person's DNA ran from 1990 to 2003—involved thousandsof scientists and technicians around the world and cost $2.5 billion.
Along with clues about what causes the disease, thoseinvolved in the bipolar disorder study hope to unearth information forimproving treatment.
The NIMH study's ultimate goal is to identify genes andpathways that contribute to the risk for bipolar disorder, says Chris Gunter,director of Research Affairs at the HudsonAlpha Institute.
If successful, the NIMH study could pique the interest ofthose outside of the research community.
"We feel that completion of the grant study will provide newinsights into disease mechanisms that have the potential to catalyzebreakthroughs in bipolar disorder prevention, treatment and diagnosis," Guntertells ddn. "This could, of course,lead to collaborations between business and our academic groups."  

Lori Lesko

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