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

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.研究目的 多项遗传学研究已表明，CACNA1C基因单核苷酸多态性（Single Nucleotide Polymorphism, SNP）rs1006737与双相情感障碍（bipolar disorder, BD）及精神分裂症（schizophrenia, SZ）的病理机制相关。近期研究发现，该多态性位点与健康对照者及双相情感障碍患者的杏仁核活动增强存在关联。本研究针对双相情感障碍、精神分裂症患者及健康对照者开展功能磁共振成像（functional Magnetic Resonance Imaging, fMRI）实验，旨在探究rs1006737风险等位基因（AA/AG）携带者的杏仁核活动是否存在异常，并比较不同诊断组间的差异。 研究方法 本研究对250名受试者（其中双相情感障碍患者66名、精神分裂症患者61名、健康对照者123名，所有受试者均为北欧血统）进行了rs1006737的基因分型，所有受试者均完成了fMRI负性面孔匹配任务。统计分析采用校正了性别、年龄、诊断类别及用药状态的模型，先对全部受试者进行分析，随后再针对各诊断组分别开展统计检验。 研究结果 在全部受试者中，风险等位基因携带者的左侧杏仁核激活程度显著升高。组间分析显示，该效应仅在双相情感障碍组中具有统计学意义，其余诊断组未观察到显著效应。但双相情感障碍组与其余各组间的风险等位基因交互效应并未达到统计学显著性。 研究结论 上述结果表明，在所有诊断组别中，CACNA1C基因单核苷酸多态性rs1006737均会影响情绪加工过程中的杏仁核活动。本研究结果进一步丰富了该多态性位点多效性效应的相关研究证据，并进一步支持离子通道失调参与了双相情感障碍与精神分裂症的潜在病理机制这一观点。