Gene Variations Behind Bipolar Disorder Uncovered

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"A neuron's excitability – whether it will fire – hinges on this delicate equilibrium," Nature magazine quoted Dr. Pamela Sklar of Massachusetts General Hospital (MGH) and the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, who led the research, as saying.

"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."

Variation in a calcium channel gene found in the brain seemed to show the second strongest association with bipolar disorder

Though the researchers yet do not known whether and how the suspect genetic variation might affect the balance machinery, their study points to the possibility that bipolar disorder might stem, at least in part, from malfunction of ion channels.

"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. Improved understanding of these abnormalities could lead to new hope for the millions of Americans affected by bipolar disorder," said NIMH Director Dr. Thomas R. Insel.

Last fall, NIMH researchers 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.

Given that bipolar disorder is thought to involve many different gene variants, the researchers needed large samples to detect relatively weak signals of illness association.

With a view to boosting their odds, Sklar and colleagues pooled data from the latter two previously published and one new study of their own.

The researchers also took additional samples from the STEP-BD study and Scottish and Irish families, and controls from the NIMH Genetics Repository.

They then examines about 1.8 million sites of genetic variation in 10,596 people, including 4,387 with bipolar disorder, and found the two genes showing the strongest association among 14 disorder-associated chromosomal regions.

According to the researchers, variation in a gene called Ankyrin 3 (ANK3) showed the strongest association with bipolar disorder.

It may be recalled that a study on mice reported last year has already shown 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 seemed to show the second strongest association with bipolar disorder.

The researchers say that the 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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