National Institute of Mental Health, Bethesda, MD 20892, USA.
J Am Acad Child Adolesc Psychiatry. 2010 Jan;49(1):33-41. doi: 10.1097/00004583-201001000-00007.
Functional magnetic resonance imaging is commonly used to characterize brain activity underlying a variety of psychiatric disorders. A previous functional magnetic resonance imaging study found that amygdala activation during a face-processing task differed between pediatric patients with bipolar disorder (BD) and healthy controls. We undertook a genome-wide association study to explore the genetic architecture of this neuroimaging phenotype.
Thirty-nine patients with BD and 29 healthy controls who had previously undergone functional magnetic resonance imaging when viewing a neutral face were genotyped using a genome-wide single-nucleotide polymorphism (SNP) array. After quality control, 104,043 SNPs were tested against normalized amygdala activation scores obtained from the right and left hemispheres. Genetic association was tested with covariates to control for race and ethnicity. Patients and controls were grouped together in the primary analyses.
Right amygdala activation under the hostility contrast was most strongly associated with an SNP in the gene DOK5 (rs2023454, p = 4.88 x 10(-7), false discovery rate = 0.05). DOK5 encodes a substrate of tropomyosin-related kinase B/C receptors involved in neurotrophin signaling. This SNP accounted for about 33% of the variance in youths with BD and 12% of the variance in healthy youths. Other results (false discovery rate <50%) were also observed at SNPs near several other genes.
To our knowledge, this is the first genome-wide association study of amygdala activation in adolescents with BD. Although preliminary, these data suggest that DOK5 and perhaps several other genes influence the magnitude of amygdala activation during face processing, particularly in those with BD. Further studies are needed to replicate these findings and characterize the mechanisms involved.
功能磁共振成像常用于描述各种精神疾病患者大脑活动的特点。一项先前的功能磁共振成像研究发现，在处理面孔的任务中，双相障碍（BD）患儿和健康对照者的杏仁核激活存在差异。我们进行了一项全基因组关联研究，以探讨这种神经影像学表型的遗传结构。
对 39 名接受过观看中性面孔的功能磁共振成像检查的 BD 患儿和 29 名健康对照者进行全基因组单核苷酸多态性（SNP）芯片基因分型。经过质量控制后，对 104043 个 SNP 进行检测，以获得来自右和左半球的正常杏仁核激活评分。通过协变量进行遗传关联测试，以控制种族和民族。患者和对照者在主要分析中被分组在一起。
敌对性对比下右侧杏仁核的激活与 DOK5 基因中的一个 SNP 最相关（rs2023454，p=4.88x10(-7)，错误发现率=0.05）。DOK5 编码神经生长因子信号转导中参与原肌球蛋白相关激酶 B/C 受体的底物。该 SNP 解释了 BD 青少年中约 33%的变异和健康青少年中 12%的变异。其他结果（错误发现率<50%）也在几个其他基因附近的 SNP 中观察到。
据我们所知，这是首次对 BD 青少年杏仁核激活的全基因组关联研究。尽管初步结果表明，DOK5 可能还有其他几个基因影响面孔处理过程中杏仁核激活的幅度，尤其是在 BD 患者中。需要进一步的研究来复制这些发现并阐明涉及的机制。
