Bipolar disorder depends upon small, combined effects from variations in many different brain genes, none of which is powerful enough by itself to cause the disease, according to a new genome-wide study. Despite this revelation, this new study shows that targeting one enzyme produced by one of these altered genes could lead to development of new and more effective medications.
The research, conducted by Amber E. Baum, Francis J. McMahon, and their colleagues, is the first study to genetically scan thousands of variations in human genes to find those that are specifically associated with bipolar disorder. Even though everyone carries the same genes, small variations in their genes influence whether or not an individual gets a specific disease.
In this study, researchers compared gene variations found in the scans of 413 adults who had bipolar disorder with gene variations found in the scans of 563 healthy adults. The researchers then focused on those gene variations that occurred most often in people with bipolar disorder and examined them individually.
“This is an example of how advances in genetics research feed into practical applications. This research would not have been possible a very few years ago. We now have a new molecular target scientists can investigate in their search for better medications for bipolar disorder,” said Elias Zerhouni, director of the National Institutes of Health (NIH).
Approximately 5.7 million American adults suffer from bipolar disorder, which also is known as manic-depressive illness. Symptoms include extremes in mood, from pronounced over-excitement and elation, often coupled with extreme irritability, to severe depression. Children may also suffer from bipolar disorder — usually a more severe form than in adults. Even though most people occasionally have mood swings, the difference is that the shifts in behavior and energy levels that accompany bipolar disorder can be disabling.
Lithium and the other mood-stabilizing medications used to treat the condition often help many people. But some people do not respond to these medications, and psychiatrists need more options so that they can tailor treatments to each patient. Because people inherit different variations in their genes, these influence whether or not they respond to a particular medication. Identifying and targeting these gene variations could help scientists develop additional medications to treat bipolar disorder.
“We’re beginning to get a foothold on the genetics of this complex brain disorder,” said National Institutes of Mental Health (NIMH) Director, Thomas Insel.
As the result of this genome-wide scan, Baum and her colleagues found a gene that encodes the enzyme, diacylglycerol kinase eta or DGKH, that they correlated with bipolar disorder. The DGKH enzyme is active in a biochemical pathway through which lithium is thought to exert its therapeutic effects. However, DGKH functions at a point closer to the base of the lithium-sensitive pathway than does the protein that lithium is thought to target. As a result of this study, scientists can now develop new compounds that either act directly on the DGKH enzyme to modify its activity, or by regulating the amount of the enzyme produced by the body.
“Treatments that target just a few of these genes or the proteins they make could yield substantial benefits for patients. 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,” said McMahon, a co-author of the study.
Due to its universal approach, this study also detected several other genes that are thought to contribute to bipolar disorder. Understanding the effects that variations in these other genes on brain function could lead to explanations of the roles that they play in this condition and how it might be better prevented or treated.
The results will be published soon in the journal, Molecular Psychiatry.