Jiang Xinyue, Sultan Alysha A, Dimick Mikaela K, Zai Clement C, Kennedy James L, MacIntosh Bradley J, Goldstein Benjamin I
Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada.
Int J Bipolar Disord. 2023 Jan 13;11(1):3. doi: 10.1186/s40345-022-00281-5.
CACNA1C rs1006737 A allele, identified as a genetic risk variant for bipolar disorder (BD), is associated with anomalous functional connectivity in adults with and without BD. Studies have yet to investigate the association of CACNA1C rs1006737 with resting-state functional connectivity (rsFC) in youth BD.
Participants included 139 youth with BD-I, -II, or -not otherwise specified, ages 13-20 years, including 27 BD A-carriers, 41 BD non-carriers, 32 healthy controls (HC) A-carriers, and 39 HC non-carriers. Anterior cingulate cortex (ACC), amygdala, and orbitofrontal cortex (OFC) were examined as regions-of-interest in seed-to-voxel analyses. General linear models included main effects of diagnosis and rs1006737, and an interaction term, controlling for age, sex, and race.
We observed a main effect of BD diagnosis on rsFC between the right amygdala and the right occipital pole (p = 0.02), and a main effect of rs1006737 genotypes on rsFC between the right OFC and bilateral occipital cortex (p < 0.001). Two significant BD diagnosis-by-CACNA1C rs1006737 interactions were also identified. The A allele was associated with positive rsFC between the right ACC and right amygdala in BD but negative rsFC in HC (p = 0.01), and negative rsFC between the left OFC and left putamen in BD but positive rsFC in HC (p = 0.01).
This study found that the rs1006737 A allele, identified as a genetic risk variant for BD in adults, was differentially associated with rsFC in youth with BD in regions relevant to emotion, executive function, and reward. Future task-based approaches are warranted to better understand brain connectivity in relation to CACNA1C in BD.
CACNA1C基因的rs1006737 A等位基因被确定为双相情感障碍（BD）的遗传风险变异，与患有和未患有BD的成年人的异常功能连接有关。尚未有研究调查CACNA1C rs1006737与青少年BD静息态功能连接（rsFC）之间的关联。
参与者包括139名年龄在13 - 20岁的I型、II型或未另作说明的青少年BD患者，其中27名BD A等位基因携带者，41名BD非携带者，32名健康对照（HC）A等位基因携带者和39名HC非携带者。在前扣带回皮质（ACC）、杏仁核和眶额皮质（OFC）进行种子点到体素分析，将其作为感兴趣区域。通用线性模型包括诊断和rs1006737的主效应以及一个交互项，同时控制年龄、性别和种族。
我们观察到BD诊断对右侧杏仁核与右侧枕极之间的rsFC有主效应（p = 0.02），以及rs1006737基因型对右侧OFC与双侧枕叶皮质之间的rsFC有主效应（p < 0.001）。还确定了两个显著的BD诊断与CACNA1C rs1006737的交互作用。A等位基因与BD患者右侧ACC和右侧杏仁核之间的正性rsFC相关，但与HC患者的负性rsFC相关（p = 0.01），并且与BD患者左侧OFC和左侧壳核之间的负性rsFC相关，但与HC患者的正性rsFC相关（p = 0.01）。
本研究发现，在成年人中被确定为BD遗传风险变异的rs1006737 A等位基因，在与情绪、执行功能和奖赏相关的区域中，与青少年BD患者的rsFC存在差异关联。未来有必要采用基于任务的方法，以更好地理解BD中与CACNA1C相关的脑连接。
