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Eric Fakra, MD; Luke W. Hyde, MS; Adam Gorka, BS; Patrick M. Fisher, BS; Karen E. Muñoz, BS; Mark Kimak, BS; Indrani Halder, PhD; Robert E. Ferrell, PhD; Stephen B. Manuck, PhD; Ahmad R. Hariri, PhD

Arch Gen Psychiatry. 2009;66(1):33-40.

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.

Author Affiliations: CIC-UPCET, Hôpital de la Timone, Service Hospitalo–Universitaire de Psychiatrie, Hôpital Ste Marguerite, Marseille, France (Dr Fakra); and Departments of Psychiatry (Drs Fakra, Halder, Manuck, and Hariri), Psychology (Mssrs Hyde and Gorka, Ms Muñoz, and Drs Manuck and Hariri), and Human Genetics (Mr Kimak and Dr Ferrell), and Center for Neuroscience (Mr Fisher and Dr Hariri), University of Pittsburgh, Pittsburgh, Pennsylvania.

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