The Genes Behind Bipolar Disorder

We know the genes that lead to bipolar disorder. Collaboration brought success.

In 2015, my colleagues and I published a study identifying the group of genes that cause bipolar disorder (BD). By comparing the genome sequences of hundreds of affected individuals to those of unaffected family members, we found a small group of genes that are expressed in brain cells (neurons) and are known to affect the excitability of nerve cells.

This work was possible because families were willing to participate, and collaborating investigators were eager to share samples from carefully studied families. We devised our own custom software tools, and we had the money to pay for all the DNA sequencing.

The data told us that no single gene causes BD. Instead, the results implied that several causative genes act together in a network that leads to the emergence of symptoms. Some of the genes we found in people with BD have turned up in studies on autism and schizophrenia, where gene networks have also been implicated.

My colleagues at the Institute for Systems Biology in Seattle developed sensitive yet efficient software for studying the entire sequence of a human genome, all 3 billion letters. The quality of the DNA sequence data was so good that we could reliably pinpoint even a single DNA letter change between different people. This approach was particularly powerful if applied to a family pedigree (for example, both parents and children) where children who had an illness showed a particular DNA letter change while the unaffected parents had a normal sequence and were free of the disease.

My sister was seriously affected by BD. I realized that all we needed to hunt for candidate BD genes was a collaborator with family pedigrees. I cold-called Dr. Francis McMahon, head of the National Institute of Mental Health, to ask if he might collaborate. He said, “We were going to call you,” since he knew of our work. His group provided samples from the genomes of 200 individuals from 41 families affected with BD.

By simply comparing sequences from affected to unaffected family members, we found that affected people had an increased burden of rare variants in genes having roles in the level of neuronal signaling. In total, the data identified 26 genes with roles in the level of nerve cell activity.

While this work was underway, other collaborators from leading groups around the U.S. learned of our study and sent us DNA from 3,014 cases and 1,717 controls, which were distinct from the NIH samples. The same rare sequence variants in neuronal excitability genes turned up, validating our results. A list of these genes and the names of our collaborators is in the online version of this column.

Looking back, we were lucky to ask the right questions at the right time, with marvelous support from collaborators, making it possible to identify the rare versions of certain essential brain genes and to recognize that these genes act coordinately as part of a network that leads to BD. A broader view emerges and suggests that while most people have “normal” versions of these genes, some of us may have one or two of the BD-associated genes. Since my sister had BD, she probably had many of the genes we identified. I probably share one or two of her BD genes. If so, I’d like to think this makes me an interesting but somewhat quiet person. Overall, BD is rare because the sequence changes are rare, and several genes must be affected in the same person.

How about therapy? While it is easy to visualize a gene therapy for sickle cell disease (one gene, one notorious mutation), if multiple genes that act in a concerted pathway are involved, such a therapy becomes much harder to design.

Lithium therapy was approved for BD 50 years ago, but it only helps about one-third of affected people. More recently, very large studies of people with BD or schizophrenia have identified genes that reveal previously unsuspected pathways and developmental processes. A study of over 14,000 BD samples and a similar number of normal people identified a protein (AKAP11) that is defective in BD (and schizophrenia) yet acts in the same pathway as lithium.

Since the structure of this protein is known, the door to detailed mechanistic studies in cell or animal systems is starting to open. Another large gene-based study showed that a protein (complement component 4) with a well-known role in anti-bacterial responses, also has a role in brain development, especially during adolescence when symptoms for schizophrenia often emerge. All of us probably carry one or two of the genes that are altered in BD, but that’s what makes us interesting, unique individuals.

Richard Gelinas, Ph.D., whose early work earned a Nobel prize, lives in Lakebay.

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