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. 2009 Jan;66(1):33-40.
doi: 10.1001/archpsyc.66.1.33.

Effects of HTR1A C(-1019)G on amygdala reactivity and trait anxiety

Eric Fakra  1 , Luke W Hyde, Adam Gorka, Patrick M Fisher, Karen E Muñoz, Mark Kimak, Indrani Halder, Robert E Ferrell, Stephen B Manuck, Ahmad R Hariri
Affiliations

Effects of HTR1A C(-1019)G on amygdala reactivity and trait anxiety

Eric Fakra et al. Arch Gen Psychiatry. 2009 Jan.

Abstract

Context: Serotonin 1A (5-hydroxytryptamine 1A [5-HT(1A)]) autoreceptors mediate negative feedback inhibition of serotonergic neurons and play a critical role in regulating serotonin signaling involved in shaping the functional response of major forebrain targets, such as the amygdala, supporting complex behavioral processes. A common functional variation (C[-1019]G) in the human 5-HT(1A) gene (HTR1A) represents 1 potential source of such interindividual variability. Both in vitro and in vivo, -1019G blocks transcriptional repression, leading to increased autoreceptor expression. Thus, -1019G may contribute to relatively decreased serotonin signaling at postsynaptic forebrain target sites via increased negative feedback.

Objectives: To evaluate the effects of HTR1A C(-1019)G on amygdala reactivity and to use path analyses to explore the impact of HTR1A-mediated variability in amygdala reactivity on individual differences in trait anxiety. We hypothesized that -1019G, which potentially results in decreased serotonin signaling, would be associated with relatively decreased amygdala reactivity and related trait anxiety.

Design: Imaging genetics in participants from an archival database.

Participants: Eighty-nine healthy adults.

Results: Consistent with prior findings, -1019G was associated with significantly decreased threat-related amygdala reactivity. Importantly, this effect was independent of that associated with another common functional polymorphism that affects serotonin signaling, 5-HTTLPR. While there were no direct genotype effects on trait anxiety, HTR1A C(-1019)G indirectly predicted 9.2% of interindividual variability in trait anxiety through its effects on amygdala reactivity.

Conclusions: Our findings further implicate relatively increased serotonin signaling, associated with a genetic variation that mediates increased 5-HT(1A) autoreceptors, in driving amygdala reactivity and trait anxiety. Moreover, they provide empirical documentation of the basic premise that genetic variation indirectly affects emergent behavioral processes related to psychiatric disease risk by biasing the response of underlying neural circuitries.

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Conflict of interest statement

Conflict of Interest Disclosure

The authors have no conflicts of interest or competing financial interests to disclose.

Figures

Figure 1
Figure 1. HTR1A genotype predicts amygdala reactivity
Single-subject mean (±SEM) activation values from the maximal voxel in a right amygdala cluster exhibiting an allele-load independent decrease in reactivity associated with the HTR1A -1019G (x = 20 mm, y = −3 mm, z = −20 mm; cluster size = 11 voxels; z = 2.59, PFDR-corrected < 0.05; and respectively. Nearly identical effects were indentified in a left amygdala cluster (x = −22 mm, y = −5 mm, z = −20 mm; cluster size = 20 voxels; z = 2.39, PFDR-corrected < 0.05). See text for additional details.
Figure 2
Figure 2. HTR1A genotype indirectly predicts trait anxiety through amygdala reactivity
A. Statistical parametric map illustrating the right amygdala cluster correlated with both HTR1A genotype and STAI-Trait (cluster size = 13 voxels; z = 2.86, P(FDR-corrected) = 0.022). Single-subject activation values from the maximal voxel in this cluster (x = 26, y = 1, z= −15) were entered into our path analyses. B. Path model testing indirect effects of HTR1A genotype on trait anxiety (STAI-Trait). Lines are labeled with unstandardized path coefficients and standard errors in parentheses. Coefficients above the line in bold represent values from the trimmed model while coefficients below the line in italics represent values from the full model with all paths included. Indirect effects of HTR1A genotype on trait anxiety were significant (αβ = −1.60, SE = .73, P < .05), while direct effects were non-significant and dropped from the model. e1 and e2 represents the residual variance not explained by model variables. *P < .05, **P < 0.01
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