Departments of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30329, USA.
JAMA Psychiatry. 2013 Apr;70(4):392-400. doi: 10.1001/2013.jamapsychiatry.210.
The FKBP5 gene product regulates glucocorticoid receptor (GR) sensitivity and hypothalamic-pituitary-adrenal axis functioning and has been associated with many stress-related psychiatric disorders. The study of intermediate phenotypes, such as emotion-processing biases and their neural substrates, provides a way to clarify the mechanisms by which FKBP5 dysregulation mediates risk for psychiatric disorders.
To examine whether allelic variations for a putatively functional single-nucleotide polymorphism associated with FKBP5 gene regulation (rs1360780) would relate differentially to attention bias for threat. this was measured through behavioral response on a dot probe task and hippocampal activation during task performance. Morphologic substrates of differential hippocampal response were also measured.
Cross-sectional study conducted from 2010 to 2012 examining associations between genotype, behavioral response, and neural response (using functional magnetic resonance imaging [fMRI]) on the dot probe; voxel-based morphometry and global and local shape analyses were used to measure structural differences in hippocampi between genotype groups.
Participants were recruited from primary care clinics of a publicly funded hospital in Atlanta, Georgia.
An African American cohort of adults (N = 103) was separated into 2 groups by genotype: one genotype group included carriers of the rs1360780 T allele, which has been associated with increased risk for posttraumatic stress disorder and affective disorders; the other group did not carry this allele. Behavioral data included both sexes (N = 103); the MRI cohort (n = 36) included only women.
Behavioral and fMRI (blood oxygen level-dependent) response, voxel-based morphometry, and shape analyses.
Carriers of the rs1360780 T allele showed an attention bias toward threat compared with individuals without this allele (F1,90 = 5.19, P = .02). Carriers of this allele demonstrated corresponding increases in hippocampal activation and differences in morphology; global and local shape analyses revealed alterations in hippocampal shape for TT/TC compared with CC genotype groups.
Genetic variants of FKBP5 may be associated with risk for stress-related psychiatric disorders via differential effects on hippocampal structure and function, resulting in altered attention response to perceived threat.
FKBP5 基因产物调节糖皮质激素受体 (GR) 敏感性和下丘脑-垂体-肾上腺轴功能，与许多与应激相关的精神疾病有关。中间表型（如情绪处理偏差及其神经基础）的研究为阐明 FKBP5 失调介导精神疾病风险的机制提供了一种方法。
研究 FKBP5 基因调节相关的假定功能性单核苷酸多态性（rs1360780）的等位基因变异是否与威胁注意偏向存在差异关系。通过在点探测任务中的行为反应和任务执行期间的海马激活来测量这一点。还测量了差异海马反应的形态学基质。
2010 年至 2012 年进行的横断面研究，考察了基因型、行为反应和点探测的神经反应（使用功能磁共振成像 [fMRI]）之间的关联；体素形态计量学和全局和局部形状分析用于测量基因型组之间海马结构差异。
参与者从佐治亚州亚特兰大市一家公立医院的初级保健诊所招募。
一个非裔美国人成年队列（N=103）根据基因型分为两组：一组基因型包括 rs1360780 T 等位基因携带者，该等位基因与创伤后应激障碍和情感障碍的风险增加有关；另一组不携带该等位基因。行为数据包括男女两性（N=103）；MRI 队列（n=36）仅包括女性。
行为和 fMRI（血氧水平依赖）反应、体素形态计量学和形状分析。
与不携带该等位基因的个体相比，rs1360780 T 等位基因携带者表现出对威胁的注意偏向（F1,90=5.19，P=0.02）。携带该等位基因的个体表现出海马激活增加和形态差异；全局和局部形状分析显示 TT/TC 基因型组与 CC 基因型组的海马形状发生改变。
FKBP5 的遗传变异可能通过对海马结构和功能的不同影响与应激相关的精神疾病风险相关，导致对感知威胁的注意力反应改变。
