Pursuing the function of psychiatric disease genes

Researchers at the Stanley Center for Psychiatric Research, a part of the Broad Institute, are taking on two common but complex psychiatric diseases – bipolar disorder and schizophrenia. Among the Stanley Center investigators is Jon Madison, a group leader within the Center whose work involves digging into the genetic contributions to both disorders.

Jon and his colleagues use the genetic findings from the Stanley Center to investigate the underlying biology of psychiatric diseases.“The Stanley Center has been looking for new genes linked with schizophrenia and bipolar disorder,” he says, “and we are then trying to study the functionality of these genes in psychiatric diseases.” This emphasis on finding out how genes may contribute to diseases like bipolar disorder and schizophrenia is an essential component of the Center’s mission.

In recognition of the work that Jon is doing at the Stanley Center, he was awarded a NARSAD (National Alliance for Research on Schizophrenia and Depression) Young Investigator Grant in January 2011 to develop chemical probes, called small molecules, to study ANK-3, a candidate risk gene for bipolar disorder. In August 2008, researchers from the Stanley Center and their collaborators published a paper in Nature Genetic supporting the role of ANK-3 and another gene in bipolar disorder as revealed by genome wide association studies (GWAS). Other groups have found the same result in other studies. GWAS help pinpoint the genetic differences between individuals with a particular condition, in this case bipolar disorder, with those lacking the illness. These differences may help explain why some people develop a condition while others do not.

ANK-3 encodes for ankyrin-G, a protein involved in neuronal signaling and communication between different areas in the brain. Jon and his team are working to understanding ANK-3’s involvement in disease pathways and learn more about its functional biology, including its possible role in increasing an individual’s susceptibility to bipolar disorder.

To fulfill that goal, Jon and his team are developing small molecules that bind to ANK-3 to help define how subtle changes in ANK-3 function affect the function or development of brain neurons and contribute to risk for bipolar disorder. “We view these small molecules as novel chemical probes to modulate the gene’s activity,” he explains.

Jon knows the road ahead will be long and difficult. But he is encouraged that the work of the Stanley Center will make a significant difference. “Our mission is to change how we study these diseases and identify small molecules or novel therapeutics in a rational way based on understanding the pathways, biochemistry, and biology of the genes that we’re identifying."