Researchers Pool Resources in Largest Study of Genetic Factors Leading to Bipolar Disorder Episodes

For a long time now, researchers have suspected a genetic link to bipolar disorder. But they’ve not been able to find it conclusively.

In a new study, doctors pooled resources to create the largest genetic analysis of its kind to date for bipolar disorder and discovered machinery involved in the balance of sodium and calcium in brain cells as a root cause.

“Faced with little agreement among previous studies searching for the genomic hot spots in bipolar disorder, these researchers pooled their data for maximal statistical power and unearthed surprising results,” said NIMH Director Thomas R. Insel, M.D. “Improved understanding of these abnormalities could lead to new hope for the millions of Americans affected by bipolar disorder.”

Researchers supported in part by the National Institute of Mental Health, part of the National Institutes of Health, found an association between the disorder and variation in two genes that make components of channels that manage the flow of the elements into and out of cells, including neurons.

2 Proteins at Fault in Disrupting Ions that Regulate Neuron Firings

Doctors found that two proteins may be involved in disrupting the ions that regulate whether neurons can fire properly. “Finding statistically robust associations linked to two proteins that may be involved in regulating such ion channels — and that are also thought to be targets of drugs used to clinically to treat bipolar disorder — is astonishing,” said Pamela Sklar, M.D., Ph.D., of Massachusetts General Hospital (MGH) and the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, who led the research.

Sklar, Shaun Purcell, Ph.D., also of MGH and the Stanley Center, and Nick Craddock, M.D., Ph.D., of Cardiff University and the Wellcome Trust Case Control Consortiuum in the United Kingdom and a large group of international collaborators reported on their findings online on Aug. 17 , 2008 in Nature Genetics.

In the first such genome-wide association study for bipolar disorder, NIMH researchers last fall reported the strongest signal associated with the illness in a gene that makes an enzyme involved the action of the anti-manic medication lithium. However, other chromosomal locations were most strongly associated with the disorder in two subsequent studies.

Bipolar Disorder Thought To Involve Many Gene Variants

Since bipolar disorder is thought to involve many different gene variants, each exerting relatively small effects, researchers need large samples to detect relatively weak signals of illness association.

To boost their odds, Sklar and colleagues pooled data from the latter two previously published and one new study of their own. They also added additional samples from the STEP-BD study and Scottish and Irish families, and controls from the NIMH Genetics Repository. After examining about 1.8 million sites of genetic variation in 10,596 people — including 4,387 with bipolar disorder — the researchers found the two genes showing the strongest association among 14 disorder-associated chromosomal regions.

Variation in a gene called Ankyrin 3 (ANK3) showed the strongest association with bipolar disorder. The ANK3 protein is strategically located in the first part of neuronal extensions called axons and is part of the cellular machinery that decides whether a neuron will fire. Co-authors of the paper had shown last year in mouse brain that lithium, the most common medication for preventing bipolar disorder episodes, reduces expression of ANK3.

Variation in a calcium channel gene found in the brain showed the second strongest association with bipolar disorder. This CACNA1C protein similarly regulates the influx and outflow of calcium and is the site of interaction for a hypertension medication that has also been used in the treatment of bipolar disorder.

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