FKBP5 and attention bias for threat: associations with hippocampal function and shape

Abstract

Importance: 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.

Objective: 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.

Design: 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.

Setting: Participants were recruited from primary care clinics of a publicly funded hospital in Atlanta, Georgia.

Participants: 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.

Main outcome measures: Behavioral and fMRI (blood oxygen level-dependent) response, voxel-based morphometry, and shape analyses.

Results: 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.

Conclusion: 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.

Figure 1

Attention bias (dot probe) task. A, Trial structure. Rows illustrate trials that were used to calculate threat bias and as functional magnetic resonance imaging contrast conditions. The top row displays trials in which the probe appears on the opposite side of the threatening expression (threat probe incongruent); the bottom row displays trials in which the probe appears on the same side of the threatening expression (threat probe congruent). B, Attention bias to threat as a function of FKBP5 genotype: TC/TT genotypes demonstrate attention bias toward threat, compared with CC genotype. Chart illustrates mean attention bias score (error bars indicate standard error of the mean), for threat faces (both races, combined) and separated by African American (AA) and white (W) race type, as a function of genotype group. *P<.03.

Figure 2

FKBP5 polymorphism is associated with differences in hippocampal shape. A, Local shape analyses of the left and right hippocampus. Smaller P values (false-discovery rate corrected) reflect greater spatial displacement for TC/TT vs CC genotypes. B, Cross-sectional views of the 3-dimensional hippocampal atlas used for reference. CA indicatescornu ammonis; DG,dentate gyrus; H, hilum; SM, stratum moleculare; and VHS,vestigial hippocampal sulcus.

Figure 3

FKBP5 polymorphism is associated with differential hippocampal activation during attention to threat. A, Statistical parametric maps of left and right hippocampus activation during the processing of threat probe-incongruent vs threat probe-congruent faces in TC/TT>CC genotype. Activations are shown overlaid onto a canonical T1 magnetic resonance image. The colored bar represents t scores for activations. Maximally activated voxels from the left parahippocampal gyrus (x, y, z: −36, −35, −8) and right hippocampus (x, y, z: 36, −24, −12), P<.05 (small-volume correction, family-wise error). Data are reported using the coordinate system of Talairach and Tournoux. B, Genotype differences in averaged blood oxygen level–dependent signal (contrast time series extracted from 6-mm spherical regions of interest) to this contrast condition.