Variation in the Williams syndrome GTF2I gene and anxiety proneness interactively affect prefrontal cortical response to aversive stimuli

M Jabbi, Q Chen, N Turner, P Kohn, M White, J S Kippenhan, D Dickinson, B Kolachana, V Mattay, D R Weinberger, K F Berman, M Jabbi, Q Chen, N Turner, P Kohn, M White, J S Kippenhan, D Dickinson, B Kolachana, V Mattay, D R Weinberger, K F Berman

Abstract

Characterizing the molecular mechanisms underlying the heritability of complex behavioral traits such as human anxiety remains a challenging endeavor for behavioral neuroscience. Copy-number variation (CNV) in the general transcription factor gene, GTF2I, located in the 7q11.23 chromosomal region that is hemideleted in Williams syndrome and duplicated in the 7q11.23 duplication syndrome (Dup7), is associated with gene-dose-dependent anxiety in mouse models and in both Williams syndrome and Dup7. Because of this recent preclinical and clinical identification of a genetic influence on anxiety, we examined whether sequence variation in GTF2I, specifically the single-nucleotide polymorphism rs2527367, interacts with trait and state anxiety to collectively impact neural response to anxiety-laden social stimuli. Two hundred and sixty healthy adults completed the Tridimensional Personality Questionnaire Harm Avoidance (HA) subscale, a trait measure of anxiety proneness, and underwent functional magnetic resonance imaging (fMRI) while matching aversive (fearful or angry) facial identity. We found an interaction between GTF2I allelic variations and HA that affects brain response: in individuals homozygous for the major allele, there was no correlation between HA and whole-brain response to aversive cues, whereas in heterozygotes and individuals homozygous for the minor allele, there was a positive correlation between HA sub-scores and a selective dorsolateral prefrontal cortex (DLPFC) responsivity during the processing of aversive stimuli. These results demonstrate that sequence variation in the GTF2I gene influences the relationship between trait anxiety and brain response to aversive social cues in healthy individuals, supporting a role for this neurogenetic mechanism in anxiety.

Trial registration: ClinicalTrials.gov NCT00004571.

Figures

Figure 1
Figure 1
Voxel-wise brain response to aversive social cues>geometric shapes. (a) Whole-brain response to aversive cues independent of genotype as derived from a one-sample t-test thresholded at P<0.001; the color bar represents t-statistics. (b) DLPFC response to aversive cues as related to individual variability in anxiety proneness scores of HA centered on MNI coordinates x, y, z=51, 30, 12, thresholded at P<0.05; the color bar represents t-statistics. (c) Contrast images of the effect of GTF2I allelic variation on HA-predicted prefrontal response to aversive social cues centered on MNI coordinates x, y, z=51, 30, 12 at P=0.002, with the results masked with HA-predicted BOLD response to aversive content; the color bar represents F-statistics. DLPFC, dorsolateral prefrontal cortex; HA, harm avoidance; MNI, Montreal Neurological Institute.
Figure 2
Figure 2
Post hoc visualization plots showing the association between HA scores and DLPFC BOLD response for each GTF2I allelic variant separately. (a) Correlation plot showing no association between HA scores and DLPFC BOLD response to aversive social stimuli in individuals homozygous for the GTF2I major t/t allele. (b, c) Correlation plots show a robust positive association between HA scores and DLPFC response in GTF2I heterozygous t/c carriers and those homozygous for the minor c/c alleles, respectively. Signal values were extracted from the DLPFC cluster centered on MNI coordinates x, y, z=51, 30, 12 representing the maximal voxel in the DLPFC where BOLD response was also predicted by HA scores and their interaction with GTF2I allelic variation, as shown in Figure 1a (upper right image). DLPFC, dorsolateral prefrontal cortex; HA, harm avoidance; MNI, Montreal Neurological Institute.

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