Laboratory of NeuroGenetics, Department of Psychology & Neuroscience, Duke University, Durham, NC, USA.
Genes Brain Behav. 2012 Oct;11(7):869-78. doi: 10.1111/j.1601-183X.2012.00837.x.
Individual variation in physiological responsiveness to stress mediates risk for mental illness and is influenced by both experiential and genetic factors. Common polymorphisms in the human gene for FK506 binding protein 5 (FKBP5), which is involved in transcriptional regulation of the hypothalamic-pituitary-adrenal (HPA) axis, have been shown to interact with childhood abuse and trauma to predict stress-related psychopathology. In the current study, we examined if such gene-environment interaction effects may be related to variability in the threat-related reactivity of the amygdala, which plays a critical role in mediating physiological and behavioral adaptations to stress including modulation of the HPA axis. To this end, 139 healthy Caucasian youth completed a blood oxygen level-dependent functional magnetic resonance imaging probe of amygdala reactivity and self-report assessments of emotional neglect (EN) and other forms of maltreatment. These individuals were genotyped for 6 FKBP5 polymorphisms (rs7748266, rs1360780, rs9296158, rs3800373, rs9470080 and rs9394309) previously associated with psychopathology and/or HPA axis function. Interactions between each SNP and EN emerged such that risk alleles predicted relatively increased dorsal amygdala reactivity in the context of higher EN, even after correcting for multiple testing. Two different haplotype analyses confirmed this relationship as haplotypes with risk alleles also exhibited increased amygdala reactivity in the context of higher EN. Our results suggest that increased threat-related amygdala reactivity may represent a mechanism linking psychopathology to interactions between common genetic variants affecting HPA axis function and childhood trauma.
个体对压力的生理反应的差异介导了精神疾病的风险，并且受到经验和遗传因素的影响。人类 FK506 结合蛋白 5（FKBP5）基因的常见多态性参与了下丘脑-垂体-肾上腺（HPA）轴的转录调节，已被证明与儿童期虐待和创伤相互作用，预测与压力相关的精神病理学。在目前的研究中，我们研究了这种基因-环境相互作用是否与杏仁核威胁相关反应性的可变性有关，杏仁核在调节对压力的生理和行为适应中起着关键作用，包括调节 HPA 轴。为此，139 名健康的白种人青年完成了一项基于血氧水平依赖的杏仁核反应功能磁共振成像探针和情感忽视（EN）和其他形式的虐待的自我报告评估。这些个体的 6 个 FKBP5 多态性（rs7748266、rs1360780、rs9296158、rs3800373、rs9470080 和 rs9394309）进行了基因分型，这些多态性先前与精神病理学和/或 HPA 轴功能有关。每个 SNP 与 EN 之间的相互作用出现了这种情况，即风险等位基因预测在较高的 EN 背景下，背侧杏仁核反应性相对增加，即使在进行了多次测试校正后也是如此。两种不同的单倍型分析证实了这种关系，因为具有风险等位基因的单倍型在较高的 EN 背景下也表现出杏仁核反应性增加。我们的结果表明，增加的威胁相关杏仁核反应性可能代表了一种将精神病理学与影响 HPA 轴功能的常见遗传变异和儿童期创伤之间相互作用联系起来的机制。
