FKBP5 and emotional neglect interact to predict individual differences in amygdala reactivity
Open accessAbstract
Individual variation in physiological responsiveness to stress mediates risk for mental illness and is influenced by both experiential and genetic factors. Common polymorphisms in the human gene for FK506 binding protein 5 (FKBP5), which is involved in transcriptional regulation of the hypothalamic–pituitary–adrenal (HPA) axis, have been shown to interact with childhood abuse and trauma to predict stress‐related psychopathology. In the current study, we examined if such gene–environment interaction effects may be related to variability in the threat‐related reactivity of the amygdala, which plays a critical role in mediating physiological and behavioral adaptations to stress including modulation of the HPA axis. To this end, 139 healthy Caucasian youth completed a blood oxygen level‐dependent functional magnetic resonance imaging probe of amygdala reactivity and self‐report assessments of emotional neglect (EN) and other forms of maltreatment. These individuals were genotyped for 6 FKBP5 polymorphisms (rs7748266, rs1360780, rs9296158, rs3800373, rs9470080 and rs9394309) previously associated with psychopathology and/or HPA axis function. Interactions between each SNP and EN emerged such that risk alleles predicted relatively increased dorsal amygdala reactivity in the context of higher EN, even after correcting for multiple testing. Two different haplotype analyses confirmed this relationship as haplotypes with risk alleles also exhibited increased amygdala reactivity in the context of higher EN. Our results suggest that increased threat‐related amygdala reactivity may represent a mechanism linking psychopathology to interactions between common genetic variants affecting HPA axis function and childhood trauma.
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FKBP5 and mineralocorticoid receptor genotypes moderate amygdala volume, reactivity and connectivity of ELS/CT exposed adults.
“More importantly, there have been a number of studies suggesting a moderating effect of FKBP5 (451–453) and mineralocorticoid receptor genotypes (454) on amygdala volume, reactivity and connectivity of ELS/CT exposed adults, thus implicating HPA axis-related genes in brain development.”
From Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation (2019) · cites this paper as [451]
The Abstract reports that FKBP5 variants interacted with childhood emotional neglect to predict increased dorsal amygdala reactivity in 139 healthy youth. This source does not establish effects on amygdala volume or connectivity, or the claim's adult population; the sentence cites a separate source for mineralocorticoid receptor genotypes. No page numbers are available in our copy. (LLM, conf=0.88)
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Gunduz-Cinar, O., Brockway, E., Lederle, L., Wilcox, T., Halladay, L. R., Ding, Y., Oh, H., Busch, E. F., Kaugars, K., Flynn, S., et al. (2019) · Molecular Psychiatry · doi:10.1038/s41380-017-0003-3 · Cited by 38 · see citing works
Stevens, J. S., Ely, T. D., Sawamura, T., Guzman, D., Bradley, B., Ressler, K. J., & Jovanovic, T. (2016) · Depression and Anxiety · doi:10.1002/da.22506 · Cited by 40 · see citing works
Aust, S., Stasch, J., Jentschke, S., Alkan Härtwig, E., Koelsch, S., Heuser, I., & Bajbouj, M. (2014) · Hippocampus · doi:10.1002/hipo.22293 · Cited by 22 · see citing works
Early adversity as the prototype gene × environment interaction in mental disorders?
Martins, J., Yusupov, N., Binder, E. B., Brückl, T. M., & Czamara, D. (2022) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2022.173371 · Cited by 22 · see citing works
Gene–Environment Interactions in the Etiology of Human Violence
Laucht, M., Brandeis, D., & Zohsel, K. (2013) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2013_260 · Cited by 18 · see citing works
- Authors
- White, M. G., Bogdan, R., Fisher, P. M., Muñoz, K. E., Williamson, D. E., & Hariri, A. R.
- Affiliations
- Duke University (US)
- Center for Integrated Molecular Brain Imaging Neurobiology Research Unit Copenhagen Denmark
- University of Pittsburgh (US)
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Williamson, D. E.
- Venue
- Genes, Brain and Behavior
- Publisher
- Wiley
- Published
- 2012-10
- Volume
- 11
- Issue
- 7
- Pages
- 869-878
- ISSN
- 1601-183X (ISSN-L)
- 1601-1848
- PMC
- PMC3838302
- OpenAlex
- W1717791288
- Semantic Scholar
- a8489d4f84daaadb06c60bc00b1cc49b49afd1e7
- Cited by
- 180
- References
- 73
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 6 · 2023: 9 · 2022: 4 · 2021: 9 · 2020: 10 · 2019: 24 · 2018: 13 · 2017: 14 · 2016: 29 · 2015: 29 · 2014: 15 · 2013: 10
- FWCI
- 7.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes Brain & Behavior (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (R01AA016274)
- National Institute on Drug Abuse (R01DA033369, P30DA023026, R01DA031579)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- FKBP5, emotional neglect, amygdala reactivity, gene-environment interaction, child abuse, hypothalamic-pituitary-adrenal axis, genetic polymorphism, haplotypes, stress responsivity, youth
- MeSH terms
- Tacrolimus Binding Protein 5, Adolescent, Alleles, Amygdala, Child Abuse, Female, Haplotypes, Humans, Magnetic Resonance Imaging, Risk Factors, Stress, Psychological, Polymorphism, Single Nucleotide, Tacrolimus Binding Proteins, Gene-Environment Interaction
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