Bipolar Disorder affects 5.7 million American adults, is the sixth leading cause of disability in the world, and if untreated up to one in five cases results in death. Moreover, it’s not going anywhere. Children with a parent who has bipolar disorder are 10 times more likely to develop it themselves. As genetics explains as much as 80% of the cause of bipolar disorder, studies of genetics are the key to understanding the illness. John Kelsoe wants a brighter future for patients suffering from bipolar disorder and their children, and has devoted over 30 years to the study of genetic causal factors for bipolar disorder.

Bipolar Disorder affects 2.6% of the U.S. adult population, and results in suicide with alarming frequency. Patients with bipolar disorder find it extremely difficult to lead normal lives, and as a result bipolar disorder is the sixth leading cause of disability in the world.

The challenges on the path to improving care of patients with bipolar disorder exist mainly on two fronts. Firstly, it is difficult to diagnose what causes bipolar disorder. Many patients have to suffer with the illness for 10+ years without getting an accurate diagnosis, and since the effects of bipolar disorder are so severe, some won’t make it that far.

In addition to the diagnosis challenge, treatment is also difficult. Patients respond differently to the many medications used to treat the illness, which include mood stabilizers, antipsychotics, antidepressants and antianxiety medications. Some of the above medications can have severe side effects, so selecting the correct medication is key to therapy.

John Kelsoe, Professor of Psychiatry at the University of California San Diego, is attempting to answer questions about the cause of bipolar disorder that could help doctors improve both diagnosis and outcomes for affected individuals. Kelsoe’s work began 30 years ago, but stalled when technology couldn’t answer his questions about the specific genes that predispose people to bipolar disorder.

Now they can.

Over the last 20 years, Kelsoe’s work has been focused on using a variety of molecular genetic methods to identify the specific genes that predispose to bipolar disorder. Rapid advances in technology have made it possible to examine all genes at once, and have led to the discovery of  over 30 genes that contribute to disease. These discoveries have opened a window on the cause of bipolar disorder that will lead to new and better treatments. Ultimately, Kelsoe would like to develop a “spit” test for medication response, where genes could help doctors select the best medication.

What’s Happening in the Lab?

Genome Wide Association and Whole Genome Sequencing: Kelsoe’s teams started by studying entire families affected by bipolar disorder. Back in the 90’s the thinking was that one or two genes predisposed an individual to the illness. Today they believe that it’s more likely that thousands of genes are involved each contributing a little tiny amount to predisposition and adding up altogether to an overall level of risk, a discovery made possible by a method called genome-wide association.

The method was developed by borrowing technologies from the semiconductor industry. Scientists use photolithography to design chips that in turn measure variation in DNA at an unprecedented level of a million markers across the genome. A large international consortium of over 300 investigators was founded and directed by Kelsoe. They are about to publish a paper about the discovery of over 30 genes for bipolar disorder found in 20,000 people with the illness. Though genome-wide association identifies genes, whole genome sequencing identifies the mutations within genes. More recently, Kelsoe’s group has used whole genome sequencing to identify the mutations within the calcium channels identified by association..  

Kelsoe’s work with genome sequencing not only informs scientists and doctors about the genes that could be precursors to bipolar disorder, but can help them identify what’s happening in a bipolar brain. The theory uncovered by this research is that the neurons and brain cells in people with bipolar disorder are hyperactive. Specifically, that calcium channels in the brain are overactive and allow cells to fire too often. This theory can then be corroborated by the next stage of research for Kelsoe’s team - stem cells.

Stem Cell Research: Up until recently, researchers had no real way to study living brain cells. Now, researchers can take any cell sample from a patient, treat it with four growth factors and turn it into a stem cell. Because stem cells can become any kind of cell, they can then be treated with different growth factors that turn them into neurons.

Not only can experimenting with these cells help researchers determine how a bipolar brain works differently than a normative brain, it can also help researchers determine how a person’s brain cells respond to the medications used to treat bipolar disorder before they are even prescribed. Kelsoe’s teams made stem cells and then brain cells from patients with bipolar disorder who had either a good or poor response to lithium in the clinic. These brain cells were 3-4 times more active than normal, and strikingly, lithium reduced the cells activity but only in the cells that came from people who had responded to lithium. This discovery could lead to a test for lithium response that might reduce the number of medication trials that bipolar patients must endure. There is also data that could help doctors predict what patients will be most vulnerable to a medication’s side effects.

Collaboration

Dr. Kelsoe is currently actively engaged in genome wide association studies of bipolar disorder. He directs the Bipolar Genome Study (BiGS) which is a 13-site consortium focused on identifying genes for bipolar disorder and their relationship to clinical symptoms. He also founded and co-directed the Psychiatric GWAS Consortium for Bipolar Disorder (PGC-BD) which is an international collaborative effort designed to identify genes for bipolar disorder in a sample of over 20,000 patients. The new technological approaches described above could be game-changers for people with bipolar disorder and their families.

Dr. Kelsoe believes significant milestones can be accomplished in five years. With the requested funding, within five years the lab aims to have a stem cell model of bipolar disorder, have identified genes and mutations in them that cause bipolar disorder and identify genes unique to lithium responders in order to develop a clinically useful predictor.