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.
Highlights
Despite the high heritability estimates for bipolar disorder (BD), the molecular genetic and neurobiological mechanisms for this disorder remain poorly understood
The risk allele was significantly associated with enhanced activity in the left amygdala (x = 224, y = 0, z = 214; Z = 3.35; cluster-size = 91) in the BD group (FWE-corrected P = 0.041)
There were no Family-Wise Error (FWE)-corrected significant findings in SZ individuals or healthy controls, but the activation patterns had the same direction in all diagnostic groups for the most significant voxel in the total sample (Figure S1), and there were only nominally significant results in amygdala for the AA/AG.GG contrast and none for the opposite contrast (GG.AA/AG) in any of the groups (Table 1)
Summary
Despite the high heritability estimates for bipolar disorder (BD), the molecular genetic and neurobiological mechanisms for this disorder remain poorly understood. Recent genomewide association (GWA) studies with substantially more statistical power than former psychiatric genetic studies have provided evidence for new and promising candidate genes [1]. The CACNA1C SNP rs1006737 was first found to be associated with BD in a combined analysis of two GWA study datasets (P = 3.1561026) [2]. When adding a third sample, this CACNA1C SNP was significantly associated with BD in the combined sample of 4,387 BD cases and 6,209 healthy controls (P = 7.061028, OR = 1.181) [3]. Subsequent studies reported association between CACNA1C and schizophrenia (SZ) [4,5] and major depressive disorder (MDD) [4,6], thereby supporting the hypothesis of genetic overlap between these severe psychiatric disorders
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