Mineralocorticoid receptor Iso/Val (rs5522) genotype moderates the association between previous childhood emotional neglect and amygdala reactivity
Open accessAbstract
OBJECTIVE: The amygdala is especially reactive to threatening stimuli, and the degree of reactivity predicts individual differences in the expression of depression and anxiety. Emerging research suggests that emotional neglect during childhood as well as hypercortisolemia may lead to heightened threat-related amygdala reactivity. This raises the possibility that genetic variation affecting hypothalamic-pituitary-adrenal (HPA) axis function contributes to individual differences in amygdala reactivity, both independently and as a function of childhood emotional neglect. METHOD: This study assessed whether the mineralocorticoid receptor iso/val polymorphism (rs5522), a functional genetic variant affecting HPA axis function, influenced threat-related amygdala reactivity in 279 individuals in late childhood and early adolescence. The study also explored the extent to which any effects of the genotype on amygdala reactivity were contingent upon previous childhood emotional neglect. RESULTS: Prior childhood emotional neglect and the val allele were associated with greater amygdala reactivity. Moreover, a significant genotype-by-emotional neglect interaction was observed whereby greater amygdala reactivity in val allele carriers was independent of previous childhood emotional neglect, while greater reactivity in iso homozygotes was revealed only in the context of a history of elevated emotional neglect. At relatively low levels of previous emotional neglect, val carriers had heightened amygdala reactivity relative to iso homozygotes. CONCLUSIONS: These results suggest that relatively greater amygdala reactivity may represent a biological mechanism through which childhood adversity and functional genetic variation in HPA axis responsiveness to stress may mediate risk for psychopathology.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [454]
The Discussion (page unavailable) reports that the mineralocorticoid receptor polymorphism moderated the association between childhood emotional neglect and threat-related amygdala reactivity. But the Participants section describes 11–15-year-olds, not adults, and this paper does not establish genotype effects on amygdala volume or connectivity. The FKBP5 findings are attributed to other citations in the sentence. (LLM, conf=0.91)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Principal components analysis corrects for stratification in genome-wide association studies
Price, A. L., Patterson, N. J., Plenge, R. M., Weinblatt, M. E., Shadick, N. A., & Reich, D. (2006) · Nature Genetics · doi:10.1038/ng1847 · Cited by 10,248 · see citing works
Development and validation of a brief screening version of the Childhood Trauma Questionnaire
Bernstein, D. P., Stein, J. A., Newcomb, M. D., Walker, E., Pogge, D., Ahluvalia, T., Stokes, J., Handelsman, L., Medrano, M., Desmond, D., et al. (2003) · Child Abuse & Neglect · doi:10.1016/s0145-2134(02)00541-0 · Cited by 6,419 · see citing works
Effects of stress throughout the lifespan on the brain, behaviour and cognition
Lupien, S. J., McEwen, B. S., Gunnar, M. R., & Heim, C. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2639 · Cited by 6,256 · see citing works
Variations in pattern of pubertal changes in girls
Marshall, W. A., & Tanner, J. M. (1969) · Archives of Disease in Childhood · doi:10.1136/adc.44.235.291 · Cited by 5,963 · see citing works
Variations in the pattern of pubertal changes in boys
Marshall, W. A., & Tanner, J. M. (1970) · Archives of Disease in Childhood · doi:10.1136/adc.45.239.13 · Cited by 5,147 · see citing works
Stress and the brain: from adaptation to disease
de Kloet, E. R., Joëls, M., & Holsboer, F. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1683 · Cited by 4,621 · see citing works
Neural regulation of endocrine and autonomic stress responses
Ulrich-Lai, Y. M., & Herman, J. P. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2647 · Cited by 3,318 · see citing works
Hayes, A. F., & Matthes, J. (2009) · Behavior Research Methods · doi:10.3758/brm.41.3.924 · Cited by 2,452 · see citing works
Pechtel, P., & Pizzagalli, D. A. (2011) · Psychopharmacology · doi:10.1007/s00213-010-2009-2 · Cited by 1,352 · see citing works
Vulnerability genes or plasticity genes?
Belsky, J., Jonassaint, C., Pluess, M., Stanton, M., Brummett, B., & Williams, R. (2009) · Molecular Psychiatry · doi:10.1038/mp.2009.44 · Cited by 1,017 · see citing works
Binder, E. B. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.05.021 · Cited by 968 · see citing works
Tottenham, N., Hare, T. A., Quinn, B. T., McCarry, T. W., Nurse, M., Gilhooly, T., Millner, A., Galvan, A., Davidson, M. C., Eigsti, I., et al. (2010) · Developmental Science · doi:10.1111/j.1467-7687.2009.00852.x · Cited by 905 · see citing works
Costafreda, S. G., Brammer, M. J., David, A. S., & Fu, C. H. Y. (2008) · Brain Research Reviews · doi:10.1016/j.brainresrev.2007.10.012 · Cited by 772 · see citing works
Fear-potentiated startle: A neural and pharmacological analysis
Davis, M., Falls, W. A., Campeau, S., & Kim, M. (1993) · Behavioural Brain Research · doi:10.1016/0166-4328(93)90102-v · Cited by 737 · see citing works
Selective attention to facial emotion in physically abused children.
Pollak, S. D., & Tolley-Schell, S. A. (2003) · Journal of Abnormal Psychology · doi:10.1037/0021-843x.112.3.323 · Cited by 515 · see citing works
Spertus, I. L., Yehuda, R., Wong, C. M., Halligan, S., & Seremetis, S. V. (2003) · Child Abuse & Neglect · doi:10.1016/j.chiabu.2003.05.001 · Cited by 509 · see citing works
Mehta, M. A., Golembo, N. I., Nosarti, C., Colvert, E., Mota, A., Williams, S. C. R., Rutter, M., & Sonuga‐Barke, E. J. S. (2009) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2009.02084.x · Cited by 488 · see citing works
The coming out of the brain mineralocorticoid receptor
Joëls, M., Karst, H., DeRijk, R., & de Kloet, E. R. (2008) · Trends in Neurosciences · doi:10.1016/j.tins.2007.10.005 · Cited by 481 · see citing works
Elevated amygdala response to faces following early deprivation
Tottenham, N., Hare, T. A., Millner, A., Gilhooly, T., Zevin, J. D., & Casey, B. J. (2011) · Developmental Science · doi:10.1111/j.1467-7687.2010.00971.x · Cited by 468 · see citing works
Fink, L., Bernstein, D. P., Handelsman, L., Foote, J. P., & Lovejoy, M. (1995) · American Journal of Psychiatry · doi:10.1176/ajp.152.9.1329 · Cited by 453 · see citing works
Wang, A. T., Dapretto, M., Hariri, A. R., Sigman, M., & Bookheimer, S. Y. (2004) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-200404000-00015 · Cited by 364 · see citing works
Self-citationvan Marle, H. J. F., Hermans, E. J., Qin, S., & Fernández, G. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.05.014 · Cited by 317 · see citing works
fMRI studies of successful emotional memory encoding: A quantitative meta-analysis
Murty, V. P., Ritchey, M., Adcock, R. A., & LaBar, K. S. (2010) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2010.07.030 · Cited by 293 · see citing works
The neurobiology of individual differences in complex behavioral traits
Hariri, A. R. (2009) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.051508.135335 · Cited by 273 · see citing works
Self-citationMultilocus Genetic Profile for Dopamine Signaling Predicts Ventral Striatum Reactivity
Nikolova, Y. S., Ferrell, R. E., Manuck, S. B., & Hariri, A. R. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.82 · Cited by 267 · see citing works
Self-citationPayne, J. D., Jackson, E. D., Hoscheidt, S., Ryan, L., Jacobs, W. J., & Nadel, L. (2007) · Learning & Memory · doi:10.1101/lm.743507 · Cited by 248 · see citing works
Bertolino, A., Arciero, G., Rubino, V., Latorre, V., Candia, M. D., Mazzola, V., Blasi, G., Caforio, G., Hariri, A. R., Kolachana, B. S., et al. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.02.031 · Cited by 223 · see citing works
Self-citationA Common Polymorphism in the Mineralocorticoid Receptor Modulates Stress Responsiveness
DeRijk, R. H., Wüst, S., Meijer, O. C., Zennaro, M., Federenko, I. S., Hellhammer, D. H., Giacchetti, G., Vreugdenhil, E., Zitman, F. G., & de Kloet, E. R. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-0915 · Cited by 213 · see citing works
Maheu, F., Dozier, M. E., Guyer, A., Mandell, D., Peloso, E., Poeth, K., Jenness, J., Lau, J. Y. F., Ackerman, J., Pine, D., et al. (2010) · Cognitive, Affective, & Behavioral Neuroscience · doi:10.3758/cabn.10.1.34 · Cited by 208 · see citing works
Time-Dependent Effects of Corticosteroids on Human Amygdala Processing
Henckens, M. J. A. G., van Wingen, G. A., Joëls, M., & Fernández, G. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.3112-10.2010 · Cited by 191 · see citing works
Hyde, L. W., Gorka, A., Manuck, S. B., & Hariri, A. R. (2011) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2010.08.025 · Cited by 188 · see citing works
Endogenous cortisol level interacts with noradrenergic activation in the human amygdala
van Stegeren, A. H., Wolf, O. T., Everaerd, W. T. A. M., Scheltens, P., Barkhof, F., & Rombouts, S. A. R. B. (2006) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2006.05.008 · Cited by 170 · see citing works
Kuningas, M., Rijk, R. H. D., Westendorp, R. G. J., Jolles, J., Slagboom, P. E., & van Heemst, D. (2006) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301260 · Cited by 129 · see citing works
Karst, H., Nair, S., Velzing, E. H., Essen, L. R., Slagter, E., Shinnick‐Gallagher, P., & Joëls, M. (2002) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2002.02172.x · Cited by 121 · see citing works
Childhood abuse is associated with increased startle reactivity in adulthood
Jovanović, T., Blanding, N. Q., Norrholm, S. D., Duncan, E., Bradley, B., & Ressler, K. J. (2009) · Depression and Anxiety · doi:10.1002/da.20599 · Cited by 119 · see citing works
DeRijk, R. H., van Leeuwen, N., Klok, M. D., & Zitman, F. G. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.03.012 · Cited by 117 · see citing works
Gass, P., Reichardt, H. M., Strekalova, T. V., Henn, F. A., & Tronche, F. (2001) · Physiology & Behavior · doi:10.1016/s0031-9384(01)00518-2 · Cited by 117 · see citing works
Gunnar, M. R., Kryzer, E. M., Ryzin, M. J. V., & Phillips, D. A. (2010) · Child Development · doi:10.1111/j.1467-8624.2010.01438.x · Cited by 109 · see citing works
Amygdala activity correlates with attentional bias in PTSD
Khoury-Malhame, M. E., Reynaud, E., Soriano, A., Michael, K., Salgado‐Pineda, P., Zendjidjian, X. Y., Gellato, C., Fakra, É., Lefebvre, M., Rouby, F., et al. (2011) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2011.03.025 · Cited by 104 · see citing works
Understanding risk for psychopathology through imaging gene–environment interactions
Hyde, L. W., Bogdan, R., & Hariri, A. R. (2011) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2011.07.001 · Cited by 102 · see citing works
Self-citationBehavioral and neural representation of emotional facial expressions across the lifespan
Somerville, L., Fani, N., & McClure-Tone, E. B. (2011) · Developmental Neuropsychology · doi:10.1080/87565641.2010.549865 · Cited by 99 · see citing works
Modeling a Negative Response Bias in the Human Amygdala by Noradrenergic–Glucocorticoid Interactions
Kukolja, J., Schlaepfer, T. E., Keysers, C., Klingmüller, D., Maier, W., Fink, G. R., & Hurlemann, R. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.3592-08.2008 · Cited by 96 · see citing works
Carré, J. M., Fisher, P. M., Manuck, S. B., & Hariri, A. R. (2010) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsq101 · Cited by 96 · see citing works
Self-citationMitra, R., Ferguson, D., & Sapolsky, R. M. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.04.016 · Cited by 87 · see citing works
van Leeuwen, N., Kumsta, R., Entringer, S., de Kloet, E. R., Zitman, F. G., DeRijk, R. H., & Wüst, S. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.07.006 · Cited by 81 · see citing works
The impact of mineralocorticoid receptor ISO/VAL genotype (rs5522) and stress on reward learning
Bogdan, R., Perlis, R. H., Fagerness, J. A., & Pizzagalli, D. A. (2010) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2010.00600.x · Cited by 67 · see citing works
Self-citationAdamec, R. E., Blundell, J. J., & Burton, P. (2005) · Physiology & Behavior · doi:10.1016/j.physbeh.2005.06.026 · Cited by 66 · see citing works
Maheu, F., Mazzone, L., Merke, D., Keil, M., Stratakis, C., Pine, D., & Ernst, M. (2008) · Development and Psychopathology · doi:10.1017/s0954579408000564 · Cited by 65 · see citing works
The Council on Economic Affairs
FINK, P. J. (1995) · American Journal of Psychiatry · doi:10.1176/ajp.152.2.309 · Cited by 40 · see citing works
Bouma, E., Riese, H., Nolte, I. M., Oosterom, E., Verhulst, F. C., Ormel, J., & Oldehinkel, A. J. (2010) · Behavior Genetics · doi:10.1007/s10519-010-9385-6 · Cited by 33 · see citing works
Unbiased ROI selection in neuroimaging studies of individual differences
Viviani, R. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.10.085 · Cited by 30 · see citing works
Gillihan, S. J., Rao, H., Brennan, L. M., Wang, D. J. J., Detre, J. A., Sankoorikal, G. M. V., Brodkin, E. S., & Farah, M. J. (2011) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2011.03.003 · Cited by 20 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The effects of childhood maltreatment on brain structure, function and connectivity
Teicher, M. H., Samson, J. A., Anderson, C. M., & Ohashi, K. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.111 · Cited by 1,856 · see citing works
Annual research review: enduring neurobiological effects of childhood abuse and neglect
Teicher, M. H., & Samson, J. A. (2016) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.12507 · Cited by 1,473 · see citing works
Paradise lost: the neurobiological and clinical consequences of child abuse and neglect
Nemeroff, C. B. (2016) · Neuron · doi:10.1016/j.neuron.2016.01.019 · Cited by 768 · see citing works
Herzog, J. I., & Schmahl, C. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00420 · Cited by 583 · see citing works
Lippard, E. T. C., & Nemeroff, C. B. (2020) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.19010020 · Cited by 527 · see citing works
Agorastos, A., Pervanidou, P., Chrousos, G. P., & Baker, D. G. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00118 · Cited by 385 · see citing works
“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.”
BackgroundHanson, J. L., Hariri, A. R., & Williamson, D. E. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.05.010 · Cited by 338 · see citing works
Self-citationNeglect as a violation of species-expectant experience: neurodevelopmental consequences
McLaughlin, K. A., Sheridan, M. A., & Nelson, C. A. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.02.1096 · Cited by 295 · see citing works
Hein, T. C., & Monk, C. S. (2017) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.12651 · Cited by 257 · see citing works
A Neural Biomarker of Psychological Vulnerability to Future Life Stress
Swartz, J. R., Knodt, A. R., Radtke, S. R., & Hariri, A. R. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.055 · Cited by 216 · see citing works
Self-citationChildhood maltreatment: altered network centrality of cingulate, precuneus, temporal pole and insula
Teicher, M. H., Anderson, C. M., Ohashi, K., & Polcari, A. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.09.016 · Cited by 202 · see citing works
The brain mineralocorticoid receptor and stress resilience
ter Heegde, F., De Rijk, R. H., & Vinkers, C. H. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.10.022 · Cited by 187 · see citing works
White, M. G., Bogdan, R., Fisher, P. M., Muñoz, K. E., Williamson, D. E., & Hariri, A. R. (2012) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2012.00837.x · Cited by 180 · see citing works
Self-citationSwartz, J. R., Williamson, D. E., & Hariri, A. R. (2015) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2014.14020195 · Cited by 144 · see citing works
Self-citationCorral-Frías, N. S., Nikolova, Y. S., Michalski, L. J., Baranger, D. A. A., Hariri, A. R., & Bogdan, R. (2015) · Psychological Medicine · doi:10.1017/s0033291715000525 · Cited by 132 · see citing works
Otte, C., Wingenfeld, K., Kuehl, L. K., Kaczmarczyk, M., Richter, S., Quante, A., Regen, F., Bajbouj, M., Zimmermann-Viehoff, F., Wiedemann, K., et al. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2014.181 · Cited by 91 · see citing works
Effects of repeated stress on excitatory drive of basal amygdala neurons in vivo
Padival, M., Quinette, D., & Rosenkranz, J. A. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.74 · Cited by 75 · see citing works
- Authors
- Bogdan, R., Williamson, D. E., & Hariri, A. R.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Venue
- American Journal of Psychiatry
- Published
- 2012-05
- Volume
- 169
- Issue
- 5
- Pages
- 515-522
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC4700829
- OpenAlex
- W2052406842
- Cited by
- 165
- References
- 52
- Citations by year
- 2025: 6 · 2024: 6 · 2023: 13 · 2022: 8 · 2021: 8 · 2020: 6 · 2019: 13 · 2018: 22 · 2017: 17 · 2016: 17 · 2015: 23 · 2014: 8 · 2013: 12 · 2012: 5
- FWCI
- 6.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (R01AA016274)
- National Institute on Drug Abuse (R01DA033369)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Social Sciences › Psychology › Clinical Psychology › Child and Adolescent Psychosocial and Emotional Development
- Keywords
- mineralocorticoid receptor, childhood emotional neglect, amygdala reactivity, hypothalamic-pituitary-adrenal axis, gene-environment interaction, childhood adversity, hypercortisolism, depression risk, anxiety risk
- MeSH terms
- Adolescent, Alleles, Amygdala, Child, Child Abuse, Female, Genotype, Homozygote, Humans, Magnetic Resonance Imaging, Male, Receptors, Mineralocorticoid, Mutation, Missense, Functional Neuroimaging
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
