Effects of HTR1A C(−1019)G on Amygdala Reactivity and Trait Anxiety
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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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A common functional polymorphism of the 5-HT 1A gene is associated with decreased amygdala response to angry and fearful faces.
“Finally a common functional polymorphism of the 5-HT 1A gene has been associated with decreased amygdala response to angry and fearful faces (Fakra et al., 2009).”
From Affective Cognition and its Disruption in Mood Disorders (2011) · cites this paper as Fakra et al., 2009
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“The link between trait anxiety and amygdala reactivity is particularly robust and seen across many different studies and approaches (Dickie & Armony, 2008; Etkin et al., 2004; Fakra et al., 2009; Haas, Omura, Constable, & Canli, 2007; Hariri, 2009; Killgore & Yurgelun-Todd, 2005; Most, Chun, Johnson, & Kiehl, 2006; Ra…”
BackgroundMethodInfluentialAcute stress modulates genotype effects on amygdala processing in humans
Cousijn, H., Rijpkema, M., Qin, S., van Marle, H. J. F., Franke, B., Hermans, E. J., van Wingen, G., & Fernández, G. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003514107 · Cited by 115 · see citing works
Albert, P., & Fiori, L. (2014) · Current Pharmaceutical Design · doi:10.2174/13816128113196660740 · Cited by 46 · see citing works
Bortolozzi, A., Manashirov, S., Chen, A., & Artigas, F. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107873 · Cited by 37 · see citing works
Lee, B. ‐., Lee, H. ‐., Lee, B. ‐., Pae, C. ‐., Yoon, B. ‐., Ryu, S. ‐., Choi, I. ‐., Lee, M. ‐., & Ham, B. ‐. (2009) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2009.00500.x · Cited by 11 · see citing works
- Authors
- Fakra, E., Hyde, L. W., Gorka, A., Fisher, P. M., Muñoz, K. E., Kimak, M., Halder, I., Ferrell, R. E., Manuck, S. B., & Hariri, A. R.
- Affiliations
- University of Pittsburgh (US)
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2009-01-01
- Volume
- 66
- Issue
- 1
- Pages
- 33
- ISSN
- 0003-990X (ISSN-L)
- PMC
- PMC2736132
- OpenAlex
- W2135290698
- Cited by
- 159
- References
- 80
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 8 · 2021: 6 · 2020: 2 · 2019: 7 · 2018: 3 · 2017: 7 · 2016: 5 · 2015: 12 · 2014: 18 · 2013: 17 · 2012: 17
- FWCI
- 9.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL040962, P01HL040962)
- National Institute of Mental Health (MH072837, K01MH072837)
- National Institute on Drug Abuse (R90DA023420)
- National Institute of General Medical Sciences (T32GM081760)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- 5-HT1A receptor, serotonin autoreceptors, amygdala reactivity, trait anxiety, serotonin signaling, 5-HTTLPR, genetic variation, interindividual variability, imaging genetics
- MeSH terms
- Adult, Alleles, Amygdala, Anger, Anxiety Disorders, Arousal, Attention, Dominance, Cerebral, Facial Expression, Fear, Female, Genotype, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Oxygen, Pattern Recognition, Visual, Signal Transduction, Autoreceptors, Receptor, Serotonin, 5-HT1A
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