Interaction Between <emph type="ital">FKBP5</emph> and Childhood Trauma and Risk of Aggressive Behavior

Bevilacqua, Laura

doi:10.1001/archgenpsychiatry.2011.152

Cited by 137Stress Responses and CortisolChild Abuse and TraumaPsychopathy, Forensic Psychiatry, Sexual Offending

Interaction Between <emph type="ital">FKBP5</emph> and Childhood Trauma and Risk of Aggressive Behavior

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Bevilacqua, Laura·2012·Archives of General Psychiatry

DOI 10.1001/archgenpsychiatry.2011.152PMC PMC3437943

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Abstract

CONTEXT: Childhood trauma may predispose individuals to aggressive behavior, and both childhood trauma and aggressive behavior are associated with hypothalamic-pituitary-adrenal axis dysregulation. OBJECTIVE: To determine whether there would be an interaction between genetic variation in FKBP5 and childhood trauma in predicting aggressive behavior. DESIGN: Cross-sectional study. Four FKBP5 single-nucleotide polymorphisms used in previous studies (rs3800373, rs9296158, rs1360780, and rs9470080) were genotyped. Three diplotypes were derived from 2 major putatively functional haplotypes regulating protein expression that were previously associated with glucocorticoid receptor sensitivity. SETTING: Penitentiary District of Abruzzo-Molise in central Italy. PARTICIPANTS: A population of 583 male Italian prisoners recruited between 2005 and 2008. MAIN OUTCOME MEASURES: A comprehensive analysis of aggression and impulsivity was undertaken using the Brown-Goodwin Lifetime History of Aggression (BGHA) questionnaire, the Buss-Durkee Hostility Inventory (BDHI), and the Barratt Impulsiveness Scale (BIS). A history of childhood trauma was investigated with the Childhood Trauma Questionnaire. The interaction between the FKBP5 diplotypes and childhood trauma on measures of aggression was analyzed. Analyses were replicated with a second behavioral measure of aggression: violent behavior in jail. Individual single-nucleotide polymorphism analysis was performed. RESULTS: Childhood trauma had a significant effect on BGHA and BDHI scores but not on BIS scores. We observed a significant influence of the FKBP5 high-expression diplotype on both a lifetime history of aggressive behavior (BGHA) (P = .012) and violent behavior in jail (P = .025) but only in individuals exposed to childhood trauma, in particular to physical abuse. No main effect of the FKBP5 diplotypes was observed. CONCLUSION: These data suggest that childhood trauma and variants in the FKBP5 gene may interact to increase the risk of overt aggressive behavior.

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Minor alleles of FKBP5 interact with ELS/CT to increase aggressive behavior, suicide attempts, and depression.
“Further clinical studies confirm minor alleles of FKBP5 being particularly sensitive and interact with ELS/CT to increase aggressive behavior (387), suicide attempts (388), and depression (389).”
From Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation (2019) · cites this paper as [387]

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Gene–Stress–Epigenetic regulation of FKBP5: clinical and translational implications
Zannas, A. S., Wiechmann, T., Gassen, N. C., & Binder, E. B. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.235 · Cited by 622 · see citing works
“…Klengel and Binder, 2013a; Koenen et al, 2005; Xie et al, 2010), suicidality (Roy et al, 2010; Roy et al, 2012), aggression and violent behaviors (Bevilacqua et al, 2012), psychosis (Collip et al, 2013), cognitive performance (Hernaus et al, 2014), and general physical illness (Lessard and…”
BackgroundInfluential
Stress and the social brain: behavioural effects and neurobiological mechanisms
Sandi, C., & Haller, J. (2015) · Nature reviews. Neuroscience · doi:10.1038/nrn3918 · Cited by 614 · see citing works
Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation
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
“Further clinical studies confirm minor alleles of FKBP5 being particularly sensitive and interact with ELS/CT to increase aggressive behavior (387), suicide attempts (388), and depression (389).”
Background
Beyond risk, resilience, and dysregulation: Phenotypic plasticity and human development
Belsky, J., & Pluess, M. (2013) · Development and Psychopathology · doi:10.1017/s095457941300059x · Cited by 363 · see citing works
“…Thompson, & Gotlib, 2010; Suzuki et al., 2011), as is the oxytocin receptor gene (OXTR; Johansson et al., 2012; Poulin, Holman, & Buffone, 2012; Sturge-Apple, Cicchetti, Davies, & Suor, 2012) and the FK506 binding protein 5 gene (Bevilacqua et al., 2012; Xie et al., 2010; Zimmermann et al., 2011).”
Hypothalamic–pituitary–adrenal axis and stress
(2020) · Handbook of Clinical Neurology · doi:10.1016/b978-0-444-64123-6.00004-7 · Cited by 279 · see citing works
Gene–environment interactions at the FKBP5 locus: sensitive periods, mechanisms and pleiotropism
Zannas, A. S., & Binder, E. B. (2013) · Genes Brain & Behavior · doi:10.1111/gbb.12104 · Cited by 268 · see citing works
“In the study by Bevilacqua et al. (2012), child abuse and FKBP5 high-induction alleles were associated with increased aggression in male prison inmates.”
Background
The effects of early life stress on the epigenome: From the womb to adulthood and even before
Provençal, N., & Binder, E. B. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2014.09.001 · Cited by 255 · see citing works
Is the HPA Axis as Target for Depression Outdated, or Is There a New Hope?
Menke, A. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00101 · Cited by 240 · see citing works
“FKBP5 has been implicated in several mental disorders and stress-related conditions such as major depression (26), bipolar disorder (28), childhood trauma and posttraumatic stress disorder (29), aggressive and suicidal behavior (30, 31).”
Background
Interaction between early-life stress and FKBP5 gene variants in major depressive disorder and post-traumatic stress disorder: A systematic review and meta-analysis
Wang, Q., Shelton, R. C., & Dwivedi, Y. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2017.08.066 · Cited by 201 · see citing works
“Similarly, gene-environment effects of FKBP5 and early-life stress have also been conducted in relation to MDD, suicide attempts, and aggression (Appel et al., 2011; Bevilacqua et al., 2012; Roy et al., 2010; Zimmermann et al., 2011).”
Background
The Influence of Gene–Environment Interactions on the Development of Alcoholism and Drug Dependence
Enoch, M. (2012) · Current Psychiatry Reports · doi:10.1007/s11920-011-0252-9 · Cited by 180 · see citing works
“ticularly physical abuse [73].”
Genetic studies of alcohol dependence in the context of the addiction cycle
Reilly, M. T., Noronha, A., Goldman, D. A., & Koob, G. F. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.01.017 · Cited by 155 · see citing works
“FK506 binding protein 5 (FKBP5), a chaperone protein that regulates HPA axis function, is implicated in severity of withdrawal, childhood trauma, aggression and suicidal behavior (Bevilacqua et al., 2012; Huang et al., 2014).”
Elevated empathy in adults following childhood trauma
Greenberg, D. M., Baron‐Cohen, S., Rosenberg, N., Fonagy, P., & Rentfrow, P. J. (2018) · PLoS ONE · doi:10.1371/journal.pone.0203886 · Cited by 148 · see citing works
FKBP5 and Attention Bias for Threat
Fani, N., Gutman, D. A., Tone, E. B., Almli, L. M., Mercer, K. B., Davis, J., Glover, E. M., Jovanović, T., Bradley, B., Dinov, I. D., et al. (2013) · JAMA Psychiatry · doi:10.1001/2013.jamapsychiatry.210 · Cited by 127 · see citing works
Early life stress and trauma: developmental neuroendocrine aspects of prolonged stress system dysregulation
Agorastos, A., Pervanidou, P., Chrousos, G. P., & Kolaitis, G. A. (2018) · HORMONES · doi:10.1007/s42000-018-0065-x · Cited by 124 · see citing works
Cingulo-insular structural alterations associated with psychogenic symptoms, childhood abuse and PTSD in functional neurological disorders
Perez, D. L., Matin, N., Barsky, A., Costumero-Ramos, V., Makaretz, S. J., Young, S. S., Sepulcre, J., LaFranceJr, W. C., Keshavan, M. S., & Dickerson, B. C. (2017) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2016-314998 · Cited by 114 · see citing works
Differential Susceptibility to Environmental Influences
Belsky, J. (2013) · International journal of child care and education policy/International journal of child care and education · doi:10.1007/2288-6729-7-2-15 · Cited by 121 · see citing works
Genetics of impulsive behaviour
Bevilacqua, L. M., & Goldman, D. A. (2013) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2012.0380 · Cited by 116 · see citing works
Self-citation
Gene—Environment Interactions in Major Depressive Disorder
Klengel, T., & Binder, E. B. (2013) · The Canadian Journal of Psychiatry · doi:10.1177/070674371305800203 · Cited by 113 · see citing works
Theranostic Biomarkers for Schizophrenia
Perković, M. N., Erjavec, G. N., Štrac, D. Š., Uzun, S., Kozumplik, O., & Pivac, N. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18040733 · Cited by 97 · see citing works
“Different SNPs of the FKBP5 and their risk genotypes (rs3800373, rs9296158, rs1360780, and rs9470080) interacted with early traumatic experiences and were associated with aggressive and violent behaviors [77].”
Background
Report of the Attorney General's National Task Force on Children Exposed to Violence
Listenbee, R. L., National Task Force on Children Exposed to Violence, Torre, J., Boyle, G., Cooper, S. W., Deer, S., Durfee, D. T., James, T. L., Lieberman, A. F., Macy, R. D., et al. (2012) · PsycEXTRA Dataset · doi:10.1037/e537692013-001 · Cited by 104 · see citing works
The prospect of FKBP51 as a drug target
Schmidt, M. V., Paez‐Pereda, M., Holsboer, F., & Hausch, F. (2012) · ChemMedChem · doi:10.1002/cmdc.201200137 · Cited by 99 · see citing works
Psychosis Prediction: Stratification of Risk Estimation With Information-Processing and Premorbid Functioning Variables
Nieman, D. H., Ruhrmann, S., Dragt, S., Soen, F., van Tricht, M. J., Koelman, J. H. T. M., Bour, L. J., Velthorst, E., Becker, H. E., Weiser, M., et al. (2013) · Schizophrenia Bulletin · doi:10.1093/schbul/sbt145 · Cited by 99 · see citing works
Cross-cultural gene− environment interactions in depression, post-traumatic stress disorder, and the cortisol awakening response:FKBP5polymorphisms and childhood trauma in South Asia
Kohrt, B. A., Worthman, C. M., Ressler, K. J., Mercer, K. B., Upadhaya, N., Koirala, S., Nepal, M. K., Sharma, V. D., & Binder, E. B. (2015) · International Review of Psychiatry · doi:10.3109/09540261.2015.1020052 · Cited by 89 · see citing works
“A study of Italian prisoners demonstrated an association with FKBP5 and aggression (Bevilacqua et al., 2012).”
BackgroundResultInfluential
Aggressive behavior in humans: Genes and pathways identified through association studies
Fernàndez‐Castillo, N., & Cormand, B. (2016) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32419 · Cited by 87 · see citing works
“Additionally, the associated gene FKBP5, mentioned in the GCAS section, encodes a protein that works as a co-chaperone of HSP90 modulating glucocorticoid receptor action [Bevilacqua et al., 2012].”
Background
Diverse structures, functions and uses of FK506 binding proteins
Bonner, J. M., & Boulianne, G. L. (2017) · Cellular Signalling · doi:10.1016/j.cellsig.2017.06.013 · Cited by 73 · see citing works
The role of limbic system irritability in linking history of childhood maltreatment and psychiatric outcomes in low-income, high-risk women: moderation by FK506 binding protein 5 haplotype
Dackis, M. N., Rogosch, F. A., Oshri, A., & Cicchetti, D. (2012) · Development and Psychopathology · doi:10.1017/s0954579412000673 · Cited by 71 · see citing works
“In a recent investigation, the presence of two CATT haplotype copies predicted aggressive and violent behavior in prison inmates exposed to childhood trauma (Bevilacqua et al., 2012).”
Background
Stress-related genes and heroin addiction: A role for a functional FKBP5 haplotype
Levran, O., Peles, E., Randesi, M., Li, Y., Rotrosen, J., Ott, J., Adelson, M., & Kreek, M. J. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.03.017 · Cited by 71 · see citing works
“Binder’s group (Binder et al., 2004, 2008; Klengel et al., 2013) identified the less abundant alleles of four SNPs (H2 haplotype, including the rs1360780T allele) to be the ‘‘risk alleles’’ that moderate child abuse-related risk for adult PTSD, in African Americans.”
Background
FKBP5 Genotype and Structural Integrity of the Posterior Cingulum
Fani, N., King, T. Z., Reiser, E., Binder, E. B., Jovanović, T., Bradley, B., & Ressler, K. J. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.322 · Cited by 68 · see citing works
Life Course Epidemiology of Trauma and Related Psychopathology in Civilian Populations
Fink, D. S., & Galea, S. (2015) · Current Psychiatry Reports · doi:10.1007/s11920-015-0566-0 · Cited by 68 · see citing works
How to measure glucocorticoid receptor’s sensitivity in patients with stress-related psychiatric disorders
Leistner, C., & Menke, A. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.01.023 · Cited by 69 · see citing works
Drug Addiction and Stress-Response Genetic Variability: Association Study in African Americans: Stress-Response Genes and Drug Addiction
Levran, O., Randesi, M., Li, Y., Rotrosen, J., Ott, J., Adelson, M., & Jeanne Kreek, M. (2014) · Annals of Human Genetics · doi:10.1111/ahg.12064 · Cited by 62 · see citing works
“FKBP5 SNP rs1360780 as well as CRHBP SNPs rs7728378 and rs1875999 were shown to interact with childhood trauma to predict depression, suicidality, aggression, or PTSD (Binder et al., 2008; Roy et al., 2010; Xie et al., 2010; Appel et al., 2011; Zimmermann et al., 2011; Bevilacqua et al., 2012).”
Disorders and borders: Psychiatric genetics and nosology
Smoller, J. W. (2013) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32174 · Cited by 66 · see citing works
“However, further researchhas reported associations with major depressive disorder and PTSD as well as suicidal behavior and aggressive and psychotic symptoms, particularly among individuals with a history of childhood trauma and stressful life events [Koenen et al., 2005; Binder et al., 2008; Brent et al., 2010; Xie e…”
Background
FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice
Huang, M., Schwandt, M. L., Chester, J. A., Kirchhoff, A. M., Kao, C., Liang, T., Tapocik, J. D., Ramchandani, V. A., George, D. T., Hodgkinson, C. A., et al. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.55 · Cited by 59 · see citing works
“…and HPA axis regulation appears to be altered, for example, the high expression alleles may instead be associated with increased GR sensitivity, in the presence of disease where feedback inhibition has been impaired along with activation of the HPA axis (Binder et al, 2004; Bevilacqua et al, 2012).”
BackgroundInfluential
Reduced functional connectivity of fronto-parietal sustained attention networks in severe childhood abuse
Hart, H. C., Lim, L. L., Mehta, M. A., Chatzieffraimidou, A., Curtis, C. J. C., Xu, X., Breen, G. D., Simmons, A., Mirza, K., & Rubia, K. (2017) · PLoS ONE · doi:10.1371/journal.pone.0188744 · Cited by 58 · see citing works
The role of hypothalamus–pituitary–adrenal genes and childhood trauma in borderline personality disorder
Martín‐Blanco, A., Ferrer, M., Soler, J., Arranz, M. J., Vega, D., Calvo, N., Elices, M., Sánchez‐Mora, C., Iris Garcia-martinez, A., Salazar, J., et al. (2015) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-015-0612-2 · Cited by 58 · see citing works
Role of FKBP5 and its genetic mutations in stress-induced psychiatric disorders: an opportunity for drug discovery
Malekpour, M., Shekouh, D., Safavinia, M. E., Shiralipour, S., Jalouli, M., Mortezanejad, S., Azarpira, N., & Ebrahimi, N. D. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1182345 · Cited by 57 · see citing works
“Additionally, Genomic Wide Association Studies (GWAS) have revealed a correlation between certain allelic variants of FKBP5 and various mental health conditions, including but not limited to aggression (29), bipolar disorders (30), suicide (31–34), post-traumatic stress disorder (PTSD) (35), negative personality trait…”
Background
Glutamatergic GRIN2B and polyaminergic ODC1 genes in suicide attempts: associations and gene–environment interactions with childhood/adolescent physical assault
Sokolowski, M., Ben-Efraim, Y. J., Wasserman, J., & Wasserman, D. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.112 · Cited by 55 · see citing works
The Disease-Associated Chaperone FKBP51 Impairs Cognitive Function by Accelerating AMPA Receptor Recycling
Blair, L. J., Criado‐Marrero, M., Zheng, D., Wang, X., Kamath, S. G., Nordhues, B. A., Weeber, E. J., & Dickey, C. A. (2019) · eNeuro · doi:10.1523/eneuro.0242-18.2019 · Cited by 47 · see citing works
“, 2014), suicide, aggression, and violent behavior (Binder et al., 2008; Bevilacqua et al., 2012).”
Background
Schizophrenia in the Spectrum of Gene-Stress Interactions: The FKBP5 Example
Daskalakis, N. P., & Binder, E. B. (2015) · Schizophrenia Bulletin · doi:10.1093/schbul/sbu189 · Cited by 44 · see citing works
The mediator roles of trait anxiety, hostility, and impulsivity in the association between childhood trauma and dissociation in male substance-dependent inpatients
Evren, C., Çınar, Ö. G., Evren, B., Ulku, M., Karabulut, V., & Umut, G. (2012) · Comprehensive Psychiatry · doi:10.1016/j.comppsych.2012.06.013 · Cited by 43 · see citing works
“Similarly childhood trauma is associated with hostility and aggressive behavior [42,43].”
Background
Associations between preterm infant stress, epigenetic alteration, telomere length and neurodevelopmental outcomes: A systematic review
Casavant, S. G., Cong, X. S., Moore, J., & Starkweather, A. R. (2019) · Early Human Development · doi:10.1016/j.earlhumdev.2019.03.003 · Cited by 41 · see citing works
Interplay between pro-inflammatory cytokines, childhood trauma, and executive function in depressed adolescents
Peters, A. T., Ren, X., Bessette, K. L., Goldstein, B. I., West, A. E., Langenecker, S. A., & Pandey, G. N. (2019) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2019.03.030 · Cited by 41 · see citing works
The variance shared across forms of childhood trauma is strongly associated with liability for psychiatric and substance use disorders
Kristjansson, S. D., McCutcheon, V. V., Arpana Agrawal, A., Lynskey, M. T., Conroy, E., Statham, D. J., Madden, P. A. F., Henders, A. K., Todorov, A. A., Bucholz, K. K., et al. (2016) · Brain and Behavior · doi:10.1002/brb3.432 · Cited by 41 · see citing works
“Many investigations have relied on binary measures to indicate the presence of a single form of trauma (e.g., Bevilacqua et al. 2012; Grabe et al. 2012a,b).”
Prenatal maternal stress and offspring aggressive behavior: Intergenerational and transgenerational inheritance
Mbiydzenyuy, N. E., Hemmings, S. M. J., & Qulu, L. (2022) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.977416 · Cited by 40 · see citing works
Impulsivity and physical aggression: examining the moderating role of anxiety.
Hatfield, J., & Dula, C. (2014) · American Journal of Psychology · doi:10.5406/amerjpsyc.127.2.0233 · Cited by 45 · see citing works
RDoC and translational perspectives on the genetics of trauma‐related psychiatric disorders
Montalvo‐Ortiz, J. L., Gelernter, J. E., Hudziak, J. J., & Kaufman, J. (2015) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32395 · Cited by 38 · see citing works
The roles of early-life adversity and rumination in neural response to emotional faces amongst anxious and depressed adults
Peters, A. T., Burkhouse, K. L., Kinney, K. L., & Phan, K. L. (2018) · Psychological Medicine · doi:10.1017/s0033291718003203 · Cited by 38 · see citing works
“Consistent with previous studies (Bernstein et al., 1997; Walker et al., 1999; Bernstein et al., 2003; Gibb et al., 2009; Johnson et al., 2011; Bevilacqua et al., 2012; Lu et al., 2013; Kudinova et al., 2015), the cut-offs of each subscale for moderate exposure which best differentiate clinically significant adversity…”
Method
The interactive effect of MAOA ‐ LPR genotype and childhood physical neglect on aggressive behaviors in Italian male prisoners
Gorodetsky, E. K., Bevilacqua, L. M., Carli, V., Sarchiapone, M., Roy, A., Goldman, D. A., & Enoch, M. (2014) · Genes Brain & Behavior · doi:10.1111/gbb.12140 · Cited by 36 · see citing works
“Since the five subscales: PA, PN, EA, EN and SA are all highly correlated in this sample (Bevilacqua et al. 2012) we”
BackgroundMethodInfluentialSelf-citation
The influence of FKBP5 genotype on expression of FKBP5 and other glucocorticoid‐regulated genes, dependent on trauma exposure
Yeo, S., Enoch, M., Gorodetsky, E. K., Akhtar, L. A., Schuebel, K. E., Roy, A., & Goldman, D. A. (2016) · Genes Brain & Behavior · doi:10.1111/gbb.12342 · Cited by 36 · see citing works
“Importantly, for the design and interpretation of DAE analyses, there is high LD across FKBP5 including between rs1360780 (A/G) and rs3800373 (G/T) (Bevilacqua et al. 2012; Binder et al. 2004; Huang et al. 2014; Roy et al. 2010).”
Background
FKBP5 polymorphisms and hypothalamic-pituitary-adrenal axis negative feedback in major depression and obsessive-compulsive disorder
Ferrer, A., Costas, J., Labad, J., Salvat-Pujol, N., Segalàs, C., Urretavizcaya, M., Real, E., de Arriba-Arnau, A., Alonso, P., Crespo, J. M., et al. (2018) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2018.08.003 · Cited by 35 · see citing works
Psychiatric symptoms in adolescents: FKBP5 genotype—early life adversity interaction effects
Comasco, E., Gustafsson, P. A., Sydsjö, G., Agnafors, S., Aho, N., & Svedin, C. G. (2015) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-015-0768-3 · Cited by 35 · see citing works
“This is in line with previous findings in adults of a FKBP5 genotypeby-childhood maltreatment interaction effect on clinical phenotypes, such as depression, PTSD, psychosis, suicide attempts, and on aggressive behaviour [18, 22, 23, 26, 28, 51, 52], suicidal tendencies, as well as on threat-related right dorsal amygda…”
The Role of FKBP5 in Mood Disorders: Action of FKBP5 on Steroid Hormone Receptors Leads to Questions About its Evolutionary Importance
JC, O. L., Zhang, B., Koren, J., Blair, L. J., & Dickey, C. A. (2013) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152731131200121 · Cited by 35 · see citing works
Gene x environment interactions in conduct disorder: Implications for future treatments
Holz, N. E., Zohsel, K., Laucht, M., Banaschewski, T., Hohmann, S., & Brandeis, D. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.08.017 · Cited by 34 · see citing works
Gene × environment interactions in the prediction of response to antidepressant treatment
Klengel, T., & Binder, E. B. (2012) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145712001459 · Cited by 34 · see citing works
“, 2010), aggression (Bevilacqua et al., 2012) and suicide attempts (Roy et al.”
Do common genotypes of FK506 binding protein 5 (FKBP5) moderate the effects of childhood maltreatment on cognition in schizophrenia and healthy controls?
Green, M. J., Raudino, A., Cairns, M. J., Wu, J. Q., Tooney, P. A., Scott, R. J., & Carr, V. J. (2015) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2015.07.019 · Cited by 31 · see citing works
“, 2010), aggression (Bevilacqua et al., 2012) and psychosis (Collip et al.”
Background
Trauma exposure interacts with impulsivity in predicting emotion regulation and depressive mood
Ceschi, G., Billieux, J., Hearn, M., Fürst, G., & der Linden, M. V. (2014) · European Journal of Psychotraumatology · doi:10.3402/ejpt.v5.24104 · Cited by 31 · see citing works
“Although contradictory findings have also been published (Bevilacqua et al., 2012), together, these results suggest that trauma and impulsivity may indeed exert a multiplier effect on interindividual cognitive emotion regulation differences.”
Result
Monitoring and predicting the risk of violence in residential facilities. No difference between patients with history or with no history of violence
de Girolamo, G., Buizza, C., Sisti, D., Ferrari, C., Bulgari, V., Iozzino, L., Boero, M. E., Cristiano, G., Francesco, A. D., Giobbio, G. M., et al. (2016) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2016.05.010 · Cited by 31 · see citing works
The emerging role of the FKBP5 gene polymorphisms in vulnerability–stress model of schizophrenia: further evidence from a Serbian population
Mihaljevic, M. M., Zeljić, K., Soldatović, I., Petrović, S. A., Mirjanić, T., Richards, A. L., Mantripragada, K. K., Pekmezovic, T. D., Novaković, I. V., & Marić, N. P. (2016) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-016-0720-7 · Cited by 30 · see citing works
“Genotypes of these functional SNPs with minor (risk) allele have been consistently associated with broad range of stress-related psychiatric disorders such as PTSD, depression, bipolar disorder, borderline personality disorder [16–21] and pathological conditions (suicide, aggressive behavior) following trauma exposure…”
BackgroundInfluential
Long-term programing of psychopathology-like behaviors in male rats by peripubertal stress depends on individual’s glucocorticoid responsiveness to stress
Walker, S. E., & Sandi, C. (2018) · Stress · doi:10.1080/10253890.2018.1435639 · Cited by 30 · see citing works
“A growing number of findings indicate that having a differential physiological sensitivity to stress may be a factor that modulates the outcome of early life stress exposure (Bevilacqua et al., 2012; Binder et al., 2008; Bryushkova et al., 2016; Klengel et al., 2013).”
Background
FKBP5 is associated with amygdala volume in the human brain and mood state: A voxel-based morphometry (VBM) study
Hirakawa, H., Akiyoshi, J., Muronaga, M., Tanaka, Y., Ishitobi, Y., Inoue, A., Oshita, H., Aizawa, S., Masuda, K., Higuma, H., et al. (2016) · International Journal of Psychiatry in Clinical Practice · doi:10.3109/13651501.2016.1144772 · Cited by 30 · see citing works
The effects of early trauma and the FKBP5 gene on PTSD and the HPA axis in a clinical sample of Gulf War veterans
Young, D. A., Inslicht, S. S., Metzler, T. J., Neylan, T. C., & Ross, J. A. (2018) · Psychiatry Research · doi:10.1016/j.psychres.2018.03.037 · Cited by 30 · see citing works
Genomic updates in understanding PTSD
Sharma, S. K., & Ressler, K. J. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.11.010 · Cited by 29 · see citing works
“(Bevilacqua et al., 2012; Binder et al., 2004; Roy et al., 2010) FKBP5 biology has also been covered extensively elsewhere.”
Background
Allostatic Load and Biomarkers of Stress in the Preterm Infant: An Integrative Review
Casavant, S. G., Cong, X. S., FITCH, R. H., Moore, J., Rosenkrantz, T. S., & Starkweather, A. R. (2019) · Biological Research For Nursing · doi:10.1177/1099800418824415 · Cited by 29 · see citing works
Examining the factors associated with impulsivity in forensic populations: A systematic review
Alford, M., O'Rourke, S., Doyle, P., & Todd, L. (2020) · Aggression and Violent Behavior · doi:10.1016/j.avb.2020.101409 · Cited by 23 · see citing works
Differential Susceptibility to Environmental Influences
Belsky, J., & Pluess, M. (2016) · Wiley eBooks · doi:10.1002/9781119125556.devpsy202 · Cited by 29 · see citing works
Psychopathological consequences of maltreatment among children and adolescents: A systematic review of the GxE literature.
Maglione, D., Caputi, M., Moretti, B., & Scaini, S. (2018) · Research in Developmental Disabilities · doi:10.1016/j.ridd.2018.06.005 · Cited by 26 · see citing works
Predictors for self‐directed aggression in Italian prisoners include externalizing behaviors, childhood trauma and the serotonin transporter gene polymorphism 5‐ HTTLPR
Gorodetsky, E. K., Carli, V., Sarchiapone, M., Roy, A., Goldman, D. A., & Enoch, M. (2016) · Genes Brain & Behavior · doi:10.1111/gbb.12293 · Cited by 27 · see citing works
“Full details of the dataset are provided in Bevilacqua et al. (2012).”
Background
FKBP5 genotype interacts with early life trauma to predict heavy drinking in college students
Lieberman, R., Armeli, S., Scott, D. M., Kranzler, H. R., Tennen, H. A., & Covault, J. (2016) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32460 · Cited by 26 · see citing works
“…conditions, including post-traumatic stress disorder (PTSD) [Binder et al., 2008], anxiety, depression [Binder et al., 2004; Lavebratt et al., 2010], addictive disorders [Huang et al., 2014; Levran et al., 2014; Jensen et al., 2015], and aggressive or violent behavior [Bevilacqua et al., 2012].”
Background
From child maltreatment to emerging adult problem drinking: Identification of a multilevel internalizing pathway among African American youth
Handley, E. D., Rogosch, F. A., & Cicchetti, D. (2017) · Development and Psychopathology · doi:10.1017/s0954579417001419 · Cited by 25 · see citing works
“…attempts (Roy, Gorodetsky, Yuan, Goldman, & Enoch, 2010; Roy, Hodgkinson, DeLuca, Goldman, & Enoch, 2012), posttraumatic stress disorder and dissociative symptoms (Xie et al., 2010; Yaylaci, Cicchetti, Rogosch, Bulut, & Hetzel, 2016), and aggressive and violent behaviors (Bevilacqua et al., 2012).”
The interactive effects of child maltreatment and the FK506 binding protein 5 gene (FKBP5) on dissociative symptoms in adolescence
Yaylaci, F. T., Cicchetti, D., Rogosch, F. A., Bulut, O., & Hetzel, S. (2016) · Development and Psychopathology · doi:10.1017/s095457941600105x · Cited by 24 · see citing works
“Only three studies to date have examined the haplotype that comprises the four SNPs we examined in the FKBP5 locus to find significant G E interactions (Bevilacqua et al., 2012; Dackis et al., 2012; Roy et al., 2010).”
Background
FKBP5 genotype and early life stress exposure predict neurobehavioral outcomes for preterm infants
D’Agata, A. L., Walsh, S. J., Vittner, D. J., Cong, X. S., McGrath, J. M., & Young, E. E. (2017) · Developmental Psychobiology · doi:10.1002/dev.21507 · Cited by 24 · see citing works
Moderators and mediators of a maternal depression treatment study: Impact of maternal trauma and parenting on child outcomes
Swartz, H. A., Cyranowski, J. M., Cheng, Y., & Amole, M. C. (2018) · Comprehensive Psychiatry · doi:10.1016/j.comppsych.2018.08.001 · Cited by 23 · see citing works
“Using previously validated cutpoints [49, 50], threshold scores were used to create five Swartz et al.”
Method
Vulnerability to inflammation-related depressive symptoms: Moderation by stress in women with breast cancer
Manigault, A. W., Kuhlman, K. R., Irwin, M. R., Cole, S. W., Ganz, P. A., Crespi, C. M., & Bower, J. E. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.03.004 · Cited by 21 · see citing works
Traumatic experiences and PTSD symptoms in substance use disorder: A comparison of recovered versus current users
Belfrage, A., Njå, A. L. M., Lunde, S., Årstad, J., Fodstad, E. C., Lid, T. G., & Erga, A. H. (2022) · Nordic Studies on Alcohol and Drugs · doi:10.1177/14550725221122222 · Cited by 22 · see citing works
“neglect (Bevilacqua et al., 2012; Erfanian, 2018; Walker et al., 1999).”
Method
Examining gene–environment interactions in comorbid depressive and disruptive behavior disorders using a Bayesian approach
Adrian, M. C., Kiff, C. J., Glazner, C., Kohen, R., Tracy, J. H., Zhou, C., McCauley, E., & Stoep, A. V. (2015) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2015.06.004 · Cited by 22 · see citing works
Co-occurring tobacco use and posttraumatic stress disorder: Smoking cessation treatment implications: Tobacco Use in Posttraumatic Stress Disorder
Kelly, M. M., Jensen, K. P., & Sofuoglu, M. (2015) · The American Journal on Addictions · doi:10.1111/ajad.12304 · Cited by 23 · see citing works
Childhood parenting and adolescent internalizing and externalizing symptoms: Moderation by multilocus hypothalamic–pituitary–adrenal axis-related genetic variation
Cao, C., & Rijlaarsdam, J. (2022) · Development and Psychopathology · doi:10.1017/s0954579421001620 · Cited by 19 · see citing works
FKBP5 variation is associated with the acute and chronic effects of nicotine
Jensen, K. P., Herman, A. I., Morean, M. E., Kranzler, H. R., Gelernter, J. E., & Sofuoglu, M. (2014) · The Pharmacogenomics Journal · doi:10.1038/tpj.2014.76 · Cited by 19 · see citing works
Childhood Abuse and Suicidal Behaviors Among Chinese Migrant Workers: The Mediating Role of Alexithymia and Social Support
Chen, L., Ngoubene-Atioky, A. J., Zanardelli, G., Deng, Y., & Yu, L. (2020) · Archives of Suicide Research · doi:10.1080/13811118.2019.1658142 · Cited by 17 · see citing works
What can HPA axis-linked genes tell us about anxiety disorders in adolescents?
Bortoluzzi, A., Blaya, C., da Rosa, E. D., Paim, M. F., Rosa, V. D. O., Leistner‐Segal, S., & Manfro, G. G. (2015) · Trends in Psychiatry and Psychotherapy · doi:10.1590/2237-6089-2015-0035 · Cited by 19 · 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
Interaction between FKBP5 variability and recent life events in the anxiety spectrum: Evidence for the differential susceptibility model
Pérez, B. P., Cristóbal-Narváez, P., Sheinbaum, T., Kwapil, T. R., Ballespí, S., Peña, E., de Castro-Català, M., Riba, M. D., Rosa, A., & Neus Barrantes-vidal, A. (2018) · PLoS ONE · doi:10.1371/journal.pone.0193044 · Cited by 18 · see citing works
Physiological Genomics Plays a Crucial Role in Response to Stressful Life Events, the Development of Aggressive Behaviours, and Post-Traumatic Stress Disorder (PTSD)
Magwai, T., & Xulu, K. R. (2022) · Genes · doi:10.3390/genes13020300 · Cited by 16 · see citing works
DNA polymorphism in the FKBP5 gene affects impulsivity in intertemporal choice
Kawamura, Y., Takahashi, T., Liu, X., Nishida, N., Tokunaga, K., Ukawa, K., Noda, Y., Yoshikawa, A., Shimada, T., Umekage, T., et al. (2013) · Asia-Pacific Psychiatry · doi:10.1111/appy.12009 · Cited by 16 · see citing works
“Furthermore, rs1360780 has been implicated in the relationship between childhood trauma and aggressive behavior (Bevilacqua et al., 2012).”
Background
Genetic and Psychosocial Predictors of Aggression: Variable Selection and Model Building With Component-Wise Gradient Boosting
Suchting, R., Gowin, J. L., Green, C. E., Walss‐Bass, C., & Lane, S. D. (2018) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00089 · Cited by 16 · see citing works
“…(Gao et al., 2015; Coccaro et al., 2016; Hsieh and Chen, 2017); biological factors, including genetic variation (Tuvblad and Baker, 2011; Bevilacqua et al., 2012; Takahashi et al., 2012; Dorfman et al., 2014); and contextual/situational factors such as substance use and provocation…”
Background
Potential role of FKBP5 single‐nucleotide polymorphisms in functional seizures
Asadi‐Pooya, A. A., Simani, L., Asadollahi, M., Rashidi, F. S., Ahmadipour, E., Alavi, A., Roozbeh, M., Akbari, N., & Firouzabadi, N. (2023) · Epilepsia Open · doi:10.1002/epi4.12716 · Cited by 15 · see citing works
A Prospective Cohort Study of Influences on Externalizing Behaviors Across Childhood: Results From a Nurse Home Visiting Randomized Controlled Trial
Enoch, M., Kitzman, H. J., Smith, J. A. V. D. L., Anson, E. A., Hodgkinson, C. A., Goldman, D. A., & Olds, D. L. (2016) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2016.02.007 · Cited by 15 · see citing works
Childhood trauma: a risk for major depression in patients with psoriasis
Erfanian, M. (2018) · Psychiatry and Clinical Psychopharmacology · doi:10.1080/24750573.2018.1452521 · Cited by 15 · see citing works
“[36], the cut-off scores for each subscale were for sexual abuse ≥8, physical abuse ≥8, emotional abuse ≥10, physical neglect ≥8, and emotional neglect ≥15.”
Background
Developmental pathways from child maltreatment to adolescent marijuana dependence: Examining moderation by FK506 binding protein 5 gene (FKBP5)
Handley, E. D., Rogosch, F. A., & Cicchetti, D. (2015) · Development and Psychopathology · doi:10.1017/s0954579415000899 · Cited by 14 · see citing works
“Although the majority of this prior work has identified FKBP5 minor alleles as conferring risk in interaction with childhood adversity (e.g., Bevilacqua et al., 2012; Binder et al., 2008; Dackis et al., 2012; Xie et al., 2010), there are a few studies that have demonstrated interactive risk…”
BackgroundInfluential
Childhood Adversity and the Association Between Stress Sensitivity and Problematic Alcohol Use in Adults
Hall, O. T., Phan, K. L., & Gorka, S. M. (2021) · Journal of Traumatic Stress · doi:10.1002/jts.22709 · Cited by 14 · see citing works
FKBP5 interacts with maltreatment in children with extreme, pervasive, and persistent aggression
Bryushkova, L., Zai, C., Chen, S., Pappa, I., Mileva, V., Tiemeier, H., Bakermans-Kranenburg, M., Kennedy, J. L., & Beitchman, J. H. (2016) · Psychiatry Research · doi:10.1016/j.psychres.2015.09.052 · Cited by 13 · see citing works
Childhood abuse history and attention bias in adults
Letkiewicz, A. M., Silton, R. L., Mimnaugh, K. J., Miller, G. A., Heller, W., Fisher, J. E., & Sass, S. M. (2020) · Psychophysiology · doi:10.1111/psyp.13627 · Cited by 13 · see citing works
The Role of Cognitive Deficits in Borderline Personality Disorder with Early Traumas: A Mediation Analysis
Bozzatello, P., Blua, C., Brasso, C., Rocca, P., & Bellino, S. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12030787 · Cited by 12 · see citing works
Resolution of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) during Nivolumab therapy for non-small cell lung cancer: a case report.
Filetti, M., Anselmi, E., Macrini, S., Rizzo, F., Iacono, D., Giusti, R., & Marchetti, P. (2018) · Seminars in Arthritis and Rheumatism · doi:10.1016/j.semarthrit.2017.12.013 · Cited by 12 · see citing works
FKBP5 haplotypes and PTSD modulate the resting-state brain activity in Han Chinese adults who lost their only child
Qi, R., Luo, Y., Zhang, L., Weng, Y., Surento, W., Jahanshad, N., Xu, Q., Yin, Y., Li, L., Cao, Z., et al. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0770-5 · Cited by 11 · see citing works
Omics Approaches to Investigate the Pathogenesis of Suicide
Boldrini, M., Xiao, Y., Singh, T., Zhu, C., Jabbi, M., Pantazopoulos, H., Gürsoy, G., Martinowich, K., Punzi, G., Vallender, E. J., et al. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2024.05.017 · Cited by 11 · see citing works
“Other useful measures include the Global Assessment Scale to assess individual level of functioning (22), recent stressful life events quanti ﬁ cation with the St. Paul Ramsey scale (23), early-life adversity history using data from a psychological autopsy (20) that parallels the Childhood Trauma Questionnaire (24), a…”
Method
Interaction between Sirtuin 1 (SIRT1) polymorphisms and childhood maltreatment on aggression risk in Chinese male adolescents
Wang, M., Peng, C., Chang, H., Yu, M., Rong, F., & Yu, Y. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.04.063 · Cited by 10 · see citing works
Saliva as a Blood Alternative for Genome-Wide DNA Methylation Profiling by Methylated DNA Immunoprecipitation (MeDIP) Sequencing
Staunstrup, N. H., Starnawska, A., Nyegaard, M., Nielsen, A. L., Børglum, A. D., & Mors, O. N. (2017) · Epigenomes · doi:10.3390/epigenomes1030014 · Cited by 10 · see citing works
“As an example to the latter, childhood maltreatment has shown to be associated with FKBP5 gene promoter hypomethylation in both brain and blood tissues [13,14].”
Background

FKBP5 interacts with maltreatment in children with extreme, pervasive, and persistent aggression
Bryushkova, L., Zai, C., Chen, S., Pappa, I., Mileva, V., Tiemeier, H., Bakermans-Kranenburg, M., Kennedy, J. L., & Beitchman, J. H. (2016) · Psychiatry Research · doi:10.1016/j.psychres.2015.09.052 · Cited by 13 · see citing works
Interaction between FKBP5 genotype and childhood trauma in predicting psychiatric disorders : a meta-analysis
Gíslason, S. S. (2020)
Interaction between FKBP5 gene and childhood trauma on psychosis, depression and anxiety symptoms in a non-clinical sample
de Castro-Català, M., Peña, E., Kwapil, T. R., Papiol, S., Sheinbaum, T., Cristóbal-Narváez, P., Ballespí, S., Barrantes‐Vidal, N., & Rosa, A. (2017) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2017.08.024 · Cited by 38 · see citing works
Predictive effect of childhood trauma and FKBP5 genotype interaction on psychiatric disorders and traits : a meta- analysis
Sverrisdóttir, E. R. (2020)
아동기 외상에서 FK506 Binding Protein 5의 유전자 환경 상호작용과 후생유전적 조절
주열 (2014) · 생물치료정신의학

Authors: Bevilacqua, L.
Affiliations: University of Molise (IT)
Corresponding author: Bevilacqua, Laura
ORCID: Bevilacqua, Laura
Venue: Archives of General Psychiatry
Publisher: American Medical Association (AMA)
Published: 2012-01-01
Volume: 69
Issue: 1
Pages: 62
ISSN: 0003-990X (ISSN-L)
DOI: 10.1001/archgenpsychiatry.2011.152
PMC: PMC3437943
OpenAlex: W2159672641
Cited by: 137
References: 66
Citations by year: 2025: 4 · 2024: 3 · 2023: 7 · 2022: 8 · 2021: 6 · 2020: 6 · 2019: 11 · 2018: 15 · 2017: 12 · 2016: 19 · 2015: 13 · 2014: 11 · 2013: 14 · 2012: 8
FWCI: 6.30
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Archives of General Psychiatry (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Archivio Istituzionale della Ricerca - Università degli Studi del Molise (submittedVersion)
Funders: National Institutes of Health
National Institute on Alcohol Abuse and Alcoholism (Z01AA000301)
National Institute on Drug Abuse (R01DA010336, R01DA10336-02)
Topics: Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
Social Sciences › Psychology › Clinical Psychology › Psychopathy, Forensic Psychiatry, Sexual Offending
Keywords: FKBP5, childhood trauma, aggression, impulsivity, gene-environment interaction, hypothalamic-pituitary-adrenal axis, glucocorticoid receptor sensitivity, physical abuse, prisoners, single nucleotide polymorphisms
MeSH terms: Tacrolimus Binding Protein 5, Adult, Aged, Aged, 80 and over, Aggression, Cross-Sectional Studies, Humans, Impulsive Behavior, Interview, Psychological, Italy, Male, Middle Aged, Prisoners, Risk Factors, Genetic Variation, Tacrolimus Binding Proteins, Adult Survivors of Child Abuse, Young Adult

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Interaction Between <emph type="ital">FKBP5</emph> and Childhood Trauma and Risk of Aggressive Behavior

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