The Effects of Genetic Background on Psychiatric Behaviors in CACNA1C +/‐ Mice

Abstract

Bipolar disorder and schizophrenia are genetic‐based psychiatric disorders. The heritability of bipolar disorder and schizophrenia, around 70% ‐ 90% and 83%, respectively, shows that the genetic variation in certain genes help leads to the development of these psychiatric disorders and that studying these genetic variations will help us understand the physiological mechanisms that lead to these psychiatric disorders. Among other genes, CACNA1C was identified as a gene, via large‐scale genome‐wide association analyses, that contributes to a person's risk for these disorders. However, the effects of the genes found only account for a small percentage of the heritable risk of these psychiatric diseases. There has been evidence that the interactions between genes, or epistasis, may account for a significant amount of the heritability. We identified different genetic interactions with CACNA1C by utilizing mouse genetics. The behavioral phenotypes of both wild‐type and CACNA1C +/‐ mice of 19 different genetic backgrounds were observed via a prepulse inhibition test. Each test measures specific behaviors that correlate to neurobiological characteristics of bipolar disorder and schizophrenia. Our data suggests that the CACNA1C +/‐ mutation has different effects on the mouse's prepulse inhibition, depending on the genetic background. The data also suggests that the CACNA1C +/‐ mutation trends toward a decreased startle response in females, while not in males. This allows us to suggest that the CACNA1C gene does undergo epistasis. In the future, we will conduct a genome‐wide association study for both trait markers and modifier markers. We will then identify high‐priority candidate modifier genes that we may be able to confirm in human data sets.