CACNA1C Risk Variant and Amygdala Activity in Bipolar Disorder, Schizophrenia and Healthy Controls

Abstract

ObjectivesSeveral genetic studies have implicated the CACNA1C SNP rs1006737 in bipolar disorder (BD) and schizophrenia (SZ) pathology. This polymorphism was recently found associated with increased amygdala activity in healthy controls and patients with BD. We performed a functional Magnetic Resonance Imaging (fMRI) study in a sample of BD and SZ cases and healthy controls to test for altered amygdala activity in carriers of the rs1006737 risk allele (AA/AG), and to investigate if there were differences across the diagnostic groups.MethodsRs1006737 was genotyped in 250 individuals (N = 66 BD, 61 SZ and 123 healthy controls), all of Northern European origin, who underwent an fMRI negative faces matching task. Statistical tests were performed with a model correcting for sex, age, diagnostic category and medication status in the total sample, and then in each diagnostic group.ResultsIn the total sample, carriers of the risk allele had increased activation in the left amygdala. Group-wise analyses showed that this effect was significant in the BD group, but not in the other diagnostic groups. However, there was no significant interaction effect for the risk allele between BD and the other groups.ConclusionsThese results indicate that CACNA1C SNP rs1006737 affects amygdala activity during emotional processing across all diagnostic groups. The current findings add to the growing body of knowledge of the pleiotropic effect of this polymorphism, and further support that ion channel dysregulation is involved in the underlying mechanisms of BD and SZ.

Genes Involved in Neurodevelopment, Neuroplasticity, and Bipolar Disorder: CACNA1C, CHRNA1, and MAPK1

“…The effect may be exerted by the rs2339104 genotype but only in the presence of the rs1034936 T allele. The effects of this particular gene have been validated in multiple different ways [39,40,41,42,43]. Variants within CACNA1C, which encodes for a subunit forming a calcium channel, may increase intracellular calcium at neuronal levels.…”

Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains

“…Resting-state functional connectivity MRI studies using blood oxygenation level-dependent signals have been helpful in identifying connectivity between distinct networks in the brain; one of these studies has demonstrated hyperconnectivity between the right amygdala and the right ventrolateral prefrontal cortex in euthymic BD subjects compared to healthy controls [109]. fMRI of BD subjects carrying the CACNA1C risk variant 1006737 displayed a significantly increased activation of the amygdala during a matching task of negative faces (expressing anger and fear) [110]. fMRI of healthy carriers and euthymic BD patients with risk-related variants at either CACNA1C rs1006737 or ANK3 rs10994336 during facial affect processing showed a reduction in connectivity between the visual and the ventral prefrontal cortical regions [111].…”

CACNA1C risk variant is associated with increased amygdala volume

“…Recent research also suggests that allelic variation within the CACNA1C gene might be associated with psychopathology via modification of the brain's function and structure. For example, the rs1006737 risk allele (A) has been associated with altered behaviour [9][10][11], brain structure [12][13][14][15] as well as brain circuits involving working memory [7,16,17], episodic memory [18][19][20][21], learning [22,23] and emotion processing [15,24,25].…”

“…One common finding implicates the rs1006737 risk allele (A) with alterations in amygdala structure and function [12,14,22,24]. Several studies have demonstrated associations between rs1006737 and amygdala volume [12,14]; however, one large study failed to find associations between rs1006737 and subcortical structures, but instead found associations between CACNA1C SNPs and brain stem volume [26].…”