Holz Nathalie E, Buchmann Arlette F, Boecker Regina, Blomeyer Dorothea, Baumeister Sarah, Wolf Isabella, Rietschel Marcella, Witt Stephanie H, Plichta Michael M, Meyer-Lindenberg Andreas, Banaschewski Tobias, Brandeis Daniel, Laucht Manfred
Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, J5, 68159, Mannheim, Germany.
Brain Struct Funct. 2015;220(3):1355-68. doi: 10.1007/s00429-014-0729-5. Epub 2014 Apr 23.
Accumulating evidence suggests a role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of depression and anxiety disorders. Based on recent findings of altered amygdala activity following childhood adversity, the present study aimed at clarifying the impact of genetic variation in FKBP5 on threat-related neural activity and coupling as well as morphometric alterations in stress-sensitive brain systems. Functional magnetic resonance imaging during an emotional face-matching task was performed in 153 healthy young adults (66 males) from a high-risk community sample followed since birth. Voxel-based morphometry was applied to study structural alterations and DNA was genotyped for FKBP5 rs1360780. Childhood adversity was measured using retrospective self-report (Childhood Trauma Questionnaire) and by a standardized parent interview assessing childhood family adversity. Depression was assessed by the Beck Depression Inventory. There was a main effect of FKBP5 on the left amygdala, with T homozygotes showing the highest activity, largest volume and increased coupling with the left hippocampus and the orbitofrontal cortex (OFC). Moreover, amygdala-OFC coupling proved to be associated with depression in this genotype. In addition, our results support previous evidence of a gene-environment interaction on right amygdala activity with respect to retrospective assessment of childhood adversity, but clarify that this does not generalize to the prospective assessment. These findings indicated that activity in T homozygotes increased with the level of adversity, whereas the opposite pattern emerged in C homozygotes, with CT individuals being intermediate. The present results point to a functional involvement of FKBP5 in intermediate phenotypes associated with emotional processing, suggesting a possible mechanism for this gene in conferring susceptibility to stress-related disorders.
越来越多的证据表明，FKBP5（一种调节糖皮质激素受体敏感性的辅助伴侣蛋白）在抑郁症和焦虑症的病因中发挥作用。基于童年逆境后杏仁核活动改变的最新研究结果，本研究旨在阐明FKBP5基因变异对与威胁相关的神经活动和耦合以及应激敏感脑系统形态计量学改变的影响。对153名自出生起就被跟踪的高危社区样本中的健康年轻成年人（66名男性）进行了情绪面孔匹配任务期间的功能磁共振成像。采用基于体素的形态计量学来研究结构改变，并对FKBP5 rs1360780进行基因分型。使用回顾性自我报告（儿童创伤问卷）和评估童年家庭逆境的标准化家长访谈来测量童年逆境。用贝克抑郁量表评估抑郁情况。FKBP5对左侧杏仁核有主要影响，T纯合子显示出最高的活动、最大的体积以及与左侧海马体和眶额皮质（OFC）的耦合增加。此外，在这种基因型中，杏仁核 - OFC耦合被证明与抑郁有关。此外，我们的结果支持了先前关于童年逆境回顾性评估中基因 - 环境相互作用对右侧杏仁核活动影响的证据，但明确这并不适用于前瞻性评估。这些发现表明，T纯合子的活动随着逆境水平的增加而增加，而C纯合子则呈现相反的模式，CT个体处于中间状态。目前的结果表明FKBP5在与情绪加工相关的中间表型中发挥功能作用，提示该基因在赋予应激相关障碍易感性方面可能存在一种机制。
