Variation in CACNA1C is Associated with Amygdala Structure and Function in Adolescents.

Abstract

Genome-wide association studies have identified allelic variation in CACNA1C as a risk factor for multiple psychiatric disorders associated with limbic system dysfunction, including bipolar disorder, schizophrenia, and depression. The CACNA1C gene codes for a subunit of L-type voltage-gated calcium channels, which modulate amygdala function. Although CACNA1C genotype appears to be associated with amygdala morphology and function in adults with and without psychopathology, whether genetic variation influences amygdala structure and function earlier in development has not been examined. In this first investigation of the neural correlates of CACNA1C in young individuals, we examined associations between two single nucleotide polymorphisms in CACNA1C (rs1006737 and rs4765914) with amygdala volume and activation during an emotional processing task in 58 adolescents and young adults 13-20 years of age. Minor (T) allele carriers of rs4765914 exhibited smaller amygdala volume than major (C) allele homozygotes (β=-0.33, p=0.006). Furthermore, minor (A) allele homozygotes of rs1006737 exhibited increased blood-oxygen-level-dependent (BOLD) signal in the amygdala when viewing negative (vs. neutral) stimuli (β=0.29, p=0.040) and decreased BOLD signal in the amygdala when instructed to downregulate their emotional response to negative stimuli (β=-0.38, p=0.009). Follow-up analyses indicated that childhood trauma did not moderate the associations of CACNA1C variation with amygdala structure and function (ps>0.170). Findings indicate that CACNA1C-related differences in amygdala structure and function are present by adolescence. However, population stratification is a concern, given the racial/ethnic heterogeneity of our sample, and our findings do not have direct clinical implications currently. Nevertheless, these results suggest that developmentally informed research can begin to shed light on the time course by which genetic liability may translate into neural differences associated with vulnerability to psychopathology.