Genetic variation in CACNA1C affects brain circuitries related to mental illness

Abstract

Context: The CACNA1C gene (alpha-1C subunit of the L-type voltage-gated calcium channel) has been identified as a risk gene for bipolar disorder and schizophrenia, but the mechanism of association has not been explored.

Objective: To identify the neural system mechanism that explains the genetic association between the CACNA1C gene and psychiatric illness using neuroimaging and human brain expression.

Design: We used blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to measure brain activation in circuitries related to bipolar disorder and schizophrenia by comparing CACNA1C genotype groups among healthy subjects. We tested the effect of genotype on messenger RNA (mRNA) levels of CACNA1C in postmortem human brain. A case-control analysis was used to determine the association of CACNA1C genotype with schizophrenia.

Setting: National Institutes of Health Clinical Center.

Patients: Healthy men and women of white race/ethnicity participated in the fMRI study. Postmortem samples from normal human brains were used for the brain expression study. Patients with schizophrenia and healthy subjects were used in the case-control analysis.

Main outcome measures: BOLD fMRI, mRNA levels in postmortem brain samples, and genetic association with schizophrenia.

Results: The risk-associated single-nucleotide polymorphism (SNP rs1006737) in CACNA1C predicted increased hippocampal activity during emotional processing (P = .001 uncorrected, P((false recovery rate [FDR])) = .05, z = 3.20) and increased prefrontal activity during executive cognition (P = 2.8e-05 uncorrected, P(FDR) = .01, z = 4.03). The risk-associated SNP also predicted increased expression of CACNA1C mRNA in human brain (P = .002). CACNA1C was associated with schizophrenia in our case-control sample (odds ratio, 1.77; P = .03).

Conclusions: The risk-associated SNP in CACNA1C maps to circuitries implicated in genetic risk for bipolar disorder and schizophrenia. Its effects in human brain expression implicate a molecular and neural system mechanism for the clinical genetic association.

Figure 1

Risk-associated allele homozygotes (AA) have a trend for greater hippocampal activity during encoding of aversive images (19 voxels [peak voxel 22, -11, -11] for the right hippocampus; 28 voxels [peak voxel -19, -15, -15] for the left hippocampus).

Figure 2

Risk allele homozygotes (AA) have prefrontal cortical inefficiency (greater activity) during the N-back working memory task (p<0.001 whole brain analysis; 88 voxels [peak voxel 54, 12, 39] for the first cluster; 20 voxels [peak voxel 33, 45, 15] for the second cluster. Red areas are significant voxels.

Figure 3

Risk-associated allele homozygotes (AA) have greater expression of CACNA1C than heterozygotes and common allele homozygotes (probe 28032) (rs2159100, P = .002 for linear regression analysis).