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Genetic Roots of Bipolar Disorder Revealed

The first genome-wide study of bipolar disorder has found that no single gene is sufficient to cause the disorder. Rather, several genetic variations appear to boost the disease risk, especially in combination. The implicated genes provide potential new targets for drug development and may ultimately lead to more effective treatments.

Bipolar disorder, also known as manic-depressive illness, affects nearly 6 million American adults and some children. It brings extreme and sometimes disabling mood swings, ranging from elation, over-excitement and irritability to crippling exhaustion and depression. Lithium and other mood-stabilizing medications help many patients cope with the disorder, but some people don't respond to current therapies. Scientists suspect that variations in inherited genes influence each person's disease risk and response to medications. By identifying these variations, researchers hope to develop new and more targeted therapies.

To detect genetic variations associated with bipolar disorder, scientists at the NIH National Institute of Mental Health (NIMH) collaborated with researchers from the Universities of Heidelberg and Bonn and several U.S. facilities to compare the genomes of adults with and without bipolar disorder. Their investigation relied on a new research method called a genome-wide association study, which involves scanning thousands of genetic markers for tiny variations that appear more often in people that have a particular condition than in those who don't.

For this study, lead investigator Dr. Francis J. McMahon of NIMH and his colleagues pooled the genetic material of adults with bipolar disorder, which allowed them to scan the entire group at a small fraction of the cost of scanning each person's genome individually. The genetic material of the healthy group was pooled and scanned separately. Altogether, the study included more than 1,200 patients with bipolar disorder and over 1,400 healthy subjects. The scientists then zeroed in on the gene variations that occurred more often in the people with bipolar disorder and examined them individually. Their results were published online on May 8, 2007, in the journal Molecular Psychiatry.

The researchers identified at least 15 genes that were significantly associated with bipolar disorder. Although each variant appeared to contribute only modestly to disease risk, the likelihood of developing bipolar disorder increased substantially among those with more variants. Variants in one particular gene called DGKH seemed to pose a greater risk than others. DGKH produces a protein that plays a key role in a biochemical pathway that is believed to give lithium its therapeutic effects.

“Treatments that target just a few of these genes or the proteins they make could yield substantial benefits for patients,” McMahon said. “Lithium is still the primary treatment for bipolar disorder, but DGKH is a promising target for new treatments that might be more effective and better tolerated.”

The researchers plan to make the results of their genome-wide scans available on a Web site, to assist other scientists who are pursuing similar lines of research.