Schizophrenia is a highly complex illness with a genetic component that has proven very difficult to pinpoint in a manner that can guide the development of more effective treatments or even lead to a cure. In a paper published by a team of researchers led by Lieber Institute for Brain Development (LIBD) Director and CEO Daniel R. Weinberger, M.D., in the July 2013 issue of The Journal of Clinical Investigation, new insight is offered into the effect of the interaction between two different schizophrenia risk genes, DISC1 andSLC12A2. The team’s work reinforces the importance of studying how genes affect one another in addition to how they act alone.
Previous studies have shown that the interaction between DISC1 and SLC12A2 affects nerve cell birth (“neurogenesis”) and development in mice. While important throughout life, the generation of new neurons is particularly critical during the earliest stages of development as the brain takes shape and “wires up.” Other work has also shown that people carrying particular risk versions (“alleles”) of both DISC1 and SLC12A2 are at greater risk for developing schizophrenia, but the alleles have not been independently linked to schizophrenia in large genome-wide association studies.
The scientists suggest that “variants without significant effects on their own interact to impair hippocampal area function and connectivity” and may ultimately bias brain development on a path to schizophrenia.”
Dr. Weinberger and team sought to identify the gene-gene interactive effect on brain activity in live subjects who carried the risk versions of both genes. The researchers conducted functional magnetic resonance imaging (fMRI) scans on 229 healthy individuals with the risk variants and measured activity in the hippocampus region of the brain, important in memory function, as they performed a task that required them to recognize an object they had seen previously. They later conducted the same experiment on 109 additional healthy individuals with the same genetic risk profile. The scans showed a significant decrease in activation of the hippocampal region and in hippocampal connectivity with the prefrontal cortex, confirming a biologic effect of this specific gene-gene interaction on human hippocampal function.
Noting that further research and analysis will be required to validate their findings, the scientists suggest that “variants without significant effects on their own interact to impair hippocampal area function and connectivity” and may ultimately bias brain development on a path to schizophrenia.” They further propose that “even minor impairment” of this kind, if it occurred early in development, could “lead to an evolutionary cascade of broader developmental effects with impact on the emergence of illnesses like schizophrenia.”
More broadly, the team noted that its findings demonstrate how it is possible to translate interactions related to basic brain developmental mechanisms “into clinically relevant” biological insights.