Study in Nature Genetics identified mutations in a calcium-channel gene and in ANK3.

An international group of scientists found a link between bipolar disorder and variations in two genes that are separately involved in the balance of sodium and calcium in brain cells.

Though the scientists do not yet know if or how the suspect genetic variation might affect this machinery, the results point to the possibility that bipolar disorder might stem, at least in part, from malfunction of ion channels.

Variation in a gene called Ankyrin 3 (ANK3) showed the strongest association with the disease. The ANK3 protein is part of the brain’s cellular machinery that decides whether a neuron will fire. Coauthors 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 also found in the brain showed the second strongest association with bipolar disorder. This CACNA1C protein 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.

Dr. Sklar and colleagues pooled data from two previously published papers 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.

“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,” states Pamela Sklar, M.D., Ph.D., of the Center for Human Genetic Research, Massachusetts General Hospital (MGH), who led the research.

The results appears in the advanced online publication of Nature Genetics on Aug 17, 2008.

Researchers from the following institutes also took part in the study: Harvard Medical School, Broad Institute of MIT and Harvard, Cardiff University, Queensland Institute of Medical Research, Birmingham University, University of Pittsburgh, Pennsylvania, University of Aberdeen, King’s College London, Trinity College Dublin, Royal Edinburgh Hospital, Windeyer Institute of Medical Sciences, Royal Victoria Infirmary, and UBC Institute of Mental Health.


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