Abstract
Rationale
Prior reviews have examined how stress, broadly defined, interacts with genetic diathesis in the pathogenesis of internalizing (i.e., depressive and anxiety) disorders. Recent findings have suggested a unique role for early life stress (ELS) in the development of internalizing disorders, contributing to the rapid proliferation of research in this area.
Objective
This paper critically reviews studies in humans examining gene–environment interaction (GxE) effects of ELS on the risk for depression and anxiety, primarily from a candidate gene perspective. Major methodological challenges that are unique to such studies are considered.
Results
The majority of published studies have focused on candidates that regulate the serotonin system, especially the serotonin transporter. More recent work has addressed interactions of ELS with candidates from the hypothalamic-pituitary-adrenal axis and neurotrophin system. Available studies vary greatly with respect to definitions of ELS, examination of gene–gene interactions, consideration of gender effects, and attention to analytic limitations.
Conclusions
Overall, there is support for GxE effects of ELS on the risk for depressive and anxiety outcomes. Future studies of ELS in this context will require careful attention to methodologic considerations. Such studies would benefit from more systematic assessment of positive environmental factors (e.g., social support) and greater utilization of developmentally sensitive paradigms.
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References
Adamec R, Burton P, Blundell J, Murphy DL, Holmes A (2006) Vulnerability to mild predator stress in serotonin transporter knockout mice. Behav Brain Res 170:126–140
Aguilera M, Arias B, Wichers M, Barrantes-Vidal N, Moya J, Villa H, van Os J, Ibanez MI, Ruiperez MA, Ortet G, Fananas L (2009) Early adversity and 5-HTT/BDNF genes: new evidence of gene × environment interactions on depressive symptoms in a general population. Psychol Med 39:1425–1432. doi:10.1017/S0033291709005248
Alexander N, Kuepper Y, Schmitz A, Osinsky R, Kozyra E, Hennig J (2009) Gene-environment interactions predict cortisol responses after acute stress: implications for the etiology of depression. Psychoneuroendocrinology 34:1294–1303
Alleva E, Francia N (2009) Psychiatric vulnerability: suggestions from animal models and role of neurotrophins. Neurosci Biobehav Rev 33:525–536
Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF (2005) Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci 8:365–371
Ansorge MS, Hen R, Gingrick JA (2007) Neurodevelopmental origins of depressive disorders. Current Opin Psychopharmacol 7:8–17
Araya R, Hu X, Heron J, Enoch M-A, Evans J, Lewis G, Nutt D, Goldman D (2009) Effects of stressful life events, maternal depression and 5-HTTLPR genotype on emotional symptoms in pre-adolescent children. Am J Med Genet B Neuropsychiatr Genet 150B:670–682
Åslund C, Leppert J, Comasco E, Nordquist N, Oreland L, Nilsson K (2009) Impact of the interaction between the 5HTTLPR polymorphism and maltreatment on adolescent depression. A population-based study. Behav Genet 39:524–531
Bagner DM, Pettit JW, Lewinsohn PM, Seeley JR (2010) Effect of maternal depression on child behavior: a sensitive period? J Am Acad Child Adolesc Psychiatry 49:699–707
Belsky J, Pluess M (2009) Beyond diathesis stress: differential susceptibility to environmental influences. Psychol Bull 135:885–908
Belsky J, Jonassaint C, Pluess M, Stanton M, Brummett B, Williams R (2009) Vulnerability genes or plasticity genes? Mol Psychiatry 14:746–754
Bet PM, Penninx BWJH, Bochdanovits Z, Uitterlinden AG, Beekman ATF, NMv S, Deeg DJH, Hoogendijk WJG (2009) Glucocorticoid receptor gene polymorphisms and childhood adversity are associated with depression: new evidence for a gene-environment interaction. Am J Med Genet B Neuropsychiatr Genet 150B:660–669
Bhatnagar S, Sun LM, Raber J, Maren S, Julius D, Dallman MF (2004) Changes in anxiety-related behaviors and hypothalamic-pituitary-adrenal activity in mice lacking the 5-HT-3A receptor. Physiol Behav 81:545–555
Biederman J, Kim JW, Doyle AE, Mick E, Fagerness J, Smoller JW, Faraone SV (2008) Sexually dimorphic effects of four genes (COMT, SLC6A2, MAOA, SLC6A4) in genetic associations of ADHD: a preliminary study. Am J Med Genet B Neuropsychiatr Genet 147B:1511–1518
Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, Tang Y, Gillespie CF, Heim CM, Nemeroff CB, Schwartz AC, Cubells JF, Ressler KJ (2008) Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. J Am Med Assoc 299:1291–1305
Bradley RG, Binder EB, Epstein MP, Tang Y, Nair HP, Liu W, Gillespie CF, Berg T, Evces M, Newport DJ, Stowe ZN, Heim CM, Nemeroff CB, Schwartz A, Cubells JF, Ressler KJ (2008) Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene. Arch Gen Psychiatry 65:190–200. doi:10.1001/archgenpsychiatry.2007.26
Bronfenbrenner U, Ceci SJ (1994) Nature-nuture reconceptualized in developmental perspective: a bioecological model. Psychol Rev 101:568–586
Brook JS, Cohen P, Brook D (1998) Longitudinal study of co-occurring psychiatric disorders and substance abuse. J Am Acad Child Adolesc Psychiatry 37:322–330
Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G (2001) Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives. Health Technol Assess 5:1–56
Brown GW, Harris TO (2008) Depression and the serotonin transporter 5-HTTLPR polymorphism: a review and a hypothesis concerning gene-environment interaction. J Affect Disord 111:1–12
Campbell-Sills L, Forde DR, Stein MB (2009) Demographic and childhood environmental predictors of resilience in a community sample. J Psychiatr Res 43:1007–1012
Carola V, Frazzetto G, Pascucci T, Audero E, Puglisi-Allegra S, Cabib S, Lesch KP, Gross C (2007) Identifying molecular substrates in a mouse mode of the serotonin transporter × environment risk factor for anxiety and depression. Biol Psychiatry 69:840–846
Caspi A, Sugden K, Moffitt T, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386–389
Caspi A, Hariri AR, Holmes A, Uher R, Moffit TE (2010) Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry 167:509–527
Charney DS (2004) Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. Am J Psychiatry 161:195–216
Chipman P, Jorm AF, Prior M, Sanson A, Smart D, Tan X, Easteal S (2007) No interaction between the serotonin transporter polymorphism (5-HTTLPR) and childhood adversity or recent stressful life events on symptoms of depression: results from two community surveys. Am J Med Genet B Neuropsychiatr Genet 144B:561–565
Chipman P, Jorm AF, Tan X, Easteal S (2010) No association between the serotonin-1A receptor gene single nucleotide polymorphism rs6295C/G and symptoms of anxiety or depression, and no interaction between the polymorphism and environmental stressors of childhood anxiety or recent stressful life events on anxiety or depression. Psychiatr Genet 20(1):8–13
Chorbov V, Lobos E, Todorov A, Heath AC, Botteron K, Todd R (2007) Relationship of 5-HTTLPR genotypes and depression risk in the presence of trauma in a female twin sample. Am J Med Genet B Neuropsychiatr Genet 144B:830–833
Cicchetti D, Rogosch FA, Sturge-Apple ML (2007) Interactions of child maltreatment and serotonin transporter and monoamine oxidase a polymorphisms: depressive symptomatology among adolescents from low socioeconomic status backgrounds. Dev Psychopathol 19:1161–1180. doi:10.1017/S0954579407000600
Cohen RA, Hitsman BL, Paul RH, McCaffery J, Stroud L, Sweet L, Gunstad J, Niaura R, Macfarlane A, Bryant RA, Gordon E (2006) Early life stress and adult emotional experience: an international perspective. Int J Psychiatry Med 36:35–52
Coplan JD, Abdallah CG, Tang CY, Mathew SJ, Martinez J, Hof PR, Smith EL, Dwork AJ, Perera TD, Pantol G, Carpenter D, Rosenblum LA, Shungu DC, Gelernter J, Kaffman A, Jackowski A, Kaufman J, Gorman JM (2010) The role of early life stress in development of the anterior limb of the internal capsule in nonhuman primates. Neurosci Lett 480:93–96
Crayton JW, Joshi I, Gulati A, Arora RC, Wolf WA (1996) Effect of corticosterone on serotonin and catecholamine receptors and uptake sites in rat frontal cortex. Brain Res 728:260–262
Danese A, Moffitt TE, Harrington H, Milne BJ, Polanczyk G, Pariante CM, Poulton R, Caspi A (2009) Adverse childhood experiences and adult risk factors for age-related disease: depression, inflammation, and clustering of metabolic risk markers. Arch Pediatr Adolesc Med 163:1135–1143. doi:10.1001/archpediatrics.2009.214
De Kloet ER, Joels M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nature Rev Neuroscience 6:463–475
Dohrenwend BP, Levav I, Shrout PE, Schwartz S, Naveh G, Link BG, Skodol AE, Stueve A (1992) Socioeconomic status and psychiatric disorders: the causation-selection issue. Science 255:946–952
Dubow EF, Ippolito MF (1994) Effects of poverty and quality of the home environment on changes in the academic and behavioral adjustment of elementary school-age children. J Clin Child Psychol 23:401–412
Duman RS (2002) Pathophysiology of depression: the concept of synaptic plasticity. Eur Psychiatry 17(Suppl 3):306–310
Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59:1116–1127
Dunlop BW, Nemeroff CB (2007) The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 64:327–337
Eaves LJ (2006) Genotype × environment interaction in psychopathology: fact or artifact? Twin Res Hum Genet 9:1–8
Eaves LJ, Silberg JL, Meyer JM, Maes HH, Simonoff E, Pickles A, Rutter M, Neale MC, Reynolds CA, Erikson MT, Heath AC, Loeber R, Truett KR, Hewitt JK (1997) Genetics and developmental psychopathology: 2. The main effects of genes and environment on behavioral problems in the Virginia twin study of adolescent behavioral development. J Child Psychol Psychiatry 38:965–980
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112:257–269
El Hage W, Powell JF, Surguladze SA (2009) Vulnerability to depression: what is the role of stress genes in gene × environment interaction? Psychol Med 39:1407–1411. doi:10.1017/S0033291709005236
Eley TC, Sugden K, Corsico A, Gregory AM, Sham P, McGuffin P, Plomin R, Craig IW (2004) Gene-environment interaction analysis of serotonin system markers with adolescent depression. Mol Psychiatry 9:908–915
Evans J, Xu K, Heron J, Enoch MA, Araya R, Lewis G, Timpson N, Davies S, Nutt D, Goldman D (2009) Emotional symptoms in children: The effect of maternal depression, life events, and COMT genotype. Am J Med Genet B 150(2):209–218
Fergusson DM, Horwood LJ (2002) Male and female offending trajectories. Dev Psychopathol 14:159–177
Fiscella K, Kitzman H (2009) Disparities in academic achievement and health: the intersection of child education and health policy. Pediatrics 123:1073–1080. doi:10.1542/peds.2008-0533
Fox NA, Hane AA, Pine DS (2007) Plasticity for affective neurocircuitry: how the environment affects gene expression. Current Directions in Psychological Science 16:1–5
Freisthler B, Gruenewald PJ, Ring L, LaScala EA (2008) An ecological assessment of the population and environmental correlates of childhood accident, assault, and child abuse injuries. Alcohol Clin Exp Res 32:1969–1975
Froger N, Palazzo E, Boni C, Hanoun N, Saurini F, Joubert C, Dutriez-Casteloot I, Enache M, Maccari S, Barden N, Cohen-Salmon C, Hamon M, Lanfumey L (2004) Neurochemical and behavioral alterations in glucocorticoid receptor-impaired transgenic mice after chronic mild stress. J Neurosci 24:2787–2796
Fu Q, Koenen KC, Miller MW, Heath AC, Bucholz KK, Lyons MJ, Eisen SA, True WR, Goldberg J, Tsuang MT (2007) Differential etiology of posttraumatic stress disorder with conduct disorder and major depression in male veterans. Biol Psychiatry 62:1088–1094
Gardner KL, Hale MW, Lightman SL, Plotsky PM, Lowry CA (2009) Adverse early life experience and social stress during adulthood interact to increase serotonin transporter mRNA expression. Brain Res 1305:47–63
Gatt JM, Nemeroff CB, Dobson-Stone C, Paul RH, Bryant RA, Schofield PR, Gordon E, Kemp AH, Williams LM (2009) Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol Psychiatry 14:681–695
Gibb BE, Uhrlass DJ, Grassia M, Benas JS, McGeary J (2009) Children‚ inferential styles, 5-HTTLPR genotype, and maternal expressed emotion-criticism: an integrated model for the intergenerational transmission of depression. J Abnorm Psychol 118:734–745
Gillespie CF, Phifer J, Bradley B, Ressler KJ (2009) Risk and resilience: genetic and environmental influences on development of the stress response. Depress Anxiety 26:984–992
Gotlib IH, Joormann J, Minor KL, Hallmayer J (2008) HPA axis reactivity: a mechanism underlying the associations among 5-HTTLPR, stress, and depression. Biol Psychiatry 63:847–851
Grahn RE, Willi MJ, Hammack SE, Maswood S, McQueen MB, Watkins LR, Maier SF (1999) Activation of serotonin-immunoreactive cells in the dorsal raphe nucleus in rats exposed to an uncontrollable stressor. Brain Res 826:35–43
Gross C, Hen R (2004) The developmental origins of anxiety. Nature Rev Neurosci 5:545–552
Gunnar M, Quevedo K (2007) The neurobiology of stress and development. Annu Rev Psychol 58:145–173. doi:10.1146/annurev.psych.58.110405.085605
Haeffel GJ, Getchell M, Koposov RA, Yrigollen CM, DeYoung CG, af Klinteberg B, Oreland L, Ruchkin VV, Grigorenko EL (2008) Association between polymorphisms in the dopamine transporter gene and depression. Evidence for a gene-environment interaction in a sample of juvenile detainees. Psychol Sci 19:62–69
Hammen C, Brennan PA, Keenan-Miller D, Hazel NA, Najman JM (2010) Chronic and acute stress, gender, and serotonin transporter gene × environment interactions predicting depression symptoms in youth. J Child Psychol Psychiatry 51:180–187
Handwerger K (2009) Differential patterns of HPA activity and reactivity in adult posttraumatic stress disorder and major depressive disorder. Harv Rev Psychiatry 17:184–205
Hardt J, Rutter M (2004) Validity of adult retrospective reports of adverse childhood experiences: review of the evidence. J Child Psychol Psychiatry 45:260–273
Hariri AR, Holmes A (2006) Genetics of emotional regulation: the role of the serotonin transporter in neural function. Trends Cogn Sci 10:182–191
Harrington R (2001) Adolescent depression—same or different? Arch Gen Psychiatry 58:21–22
Hayden EP, Klein DN, Dougherty LR, Olino TM, Laptook RS, Dyson MW et al (2010) The dopamine D2 receptor gene and depressive and anxious symptoms in childhood: associations and evidence for gene-environment correlation and gene-environment interaction. Psychiatr Genet 20(6):304–310
Heim C, Nemeroff CB (2002) Neurobiology of early life stress: clinical studies. Semin Clin Neuropsychiatry 7:147–159
Heim C, Bradley B, Mletzko TC, Deveau TC, Musselman DL, Nemeroff CB, Ressler KJ, Binder EB (2009) Effect of childhood trauma on adult depression and neuroendocrine function: sex-specific moderation by CRH receptor 1 gene. Frontiers in Behavioral Neuroscience 3:1–10
Hemrick-Luecke SK, Evans DC (2002) Comparison of the potency of MDL 100, 907 and SB 242084 in blocking the serotonin (5HT)(2) receptor agonist-induced increases in rat serum corticosterone concentrations: evidence for 5-HT(2A) receptor mediation of the HPA axis. Neuropharmacology 42:162–169
Herman JP, Ostrander MM, Mueller NK, Figueiredo H (2005) Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Prog Neuropsychopharmacol Biol Psychiatry 29:12011–1213
Hicks BM, DiRago AC, Iacono WG, McGue M (2009) Gene × environment interplay in internalizing disorders: consistent findings across six environmental risk factors. J Child Psychol Psychiatry 50:1309–1317
Holmes A (2008) Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease. Neurosci Biobehav Rev 32:1293–1314
Holmes A, Murphy DL, Crawley JN (2003) Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol Psychiatry 54:953–959
Horowitz K, McKay M, Marshall R (2005) Community violence and urban families: experiences, effects, and directions for intervention. Am J Orthopsychiatry 75:356–368
Irish L, Kobayashi I, Delahanty DL (2009) Long-term physical health consequences of childhood sexual abuse: a meta-analytic review. J Pediatr Psychol 35:450–461. doi:10.1093/jpepsy/jsp118
Jaffee SR, Moffit TE, Caspi A, Fombonne E, Poulton R, Martin J (2002) Differences in early childhood risk factors for juvenile-onset and adult-onset depression. Arch Gen Psychiatry 59:215–222
Jinks JL, Fulker DW (1970) Comparison of the biometrical genetical, MAVA, and classical approaches to the analysis of the human behavior. Psychol Bull 73:311–349
Johnson JG, Cohen P, Dohrenwend BP, Link BG, Brook JS (1999) A longitudinal investigation of social causation and social selection processes involved in the association between socioeconomic status and psychiatric disorders. J Abnorm Psychol 108:490–499
Kaufman J, Yang BZ, Douglas-Palumberi H, Houshyar S, Lipschitz D, Krystal JH, Gelernter J (2004) Social support and serotonin transporter gene moderate depression in maltreated children. Proceedings of the National Academy of Sciences 101:17316–17321
Kaufman J, Yang BZ, Douglas-Palumberi H, Grasso D, Lipschitz D, Houshyar S, Krystal JH, Gelernter J (2006) Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol Psychiatry 59:673–680
Kawachi I, Subramanian SV (2006) Measuring and modeling the social and geographic context of trauma: a multilevel modeling approach. J Trauma Stress 19:195–203
Kendler KS, Baker JS (2007) Genetic influences on measures of the environment: a systematic review. Psychol Med 37:615–626. doi:10.1017/S0033291706009524
Kendler KS, Kessler RC, Walters EE, MacLean CJ, Neale MC, Health AC, Eaves LJ (1995) Stressful life events, genetic liability and onset of an episode of major depression in women: evidence of genetic control of sensitivity to the environment. Am J Psychiatry 152:833–842
Kendler KS, Hettema JM, Butera F, Gardner CO, Prescott CA (2003) Life event dimensions of loss, humiliation, entrapment, and danger in the prediction of onsets of major depression and generalized anxiety. Arch Gen Psychiatry 60:789–796
Kessing LV, Agerbo E, Mortensen PB (2003) Does the impact of major stressful life events on the risk of developing depression change throughout life? Psychol Med 33:1177–1184
Koenen KC, Galea S (2009) Gene-environment interactions and depression. JAMA 302:1859–1862. doi:10.1001/jama.2009.1575
Koenen KC, Fu QJ, Ertel K, Lyons MJ, Eisen SA, True WR, Goldberg J, Tsuang MT (2008) Common genetic liability to major depression and posttraumatic stress disorder in men. J Affect Disord 105:109–115
Kolber BJ, Boyle MP, Wieczorek L, Kelley CL, Onwuzurike CC, Nettles SA, Vogt SK, Muglia LJ (2010) Transient early-life forebrain corticotropin-releasing hormone elevation causes long-lasting anxiogenic and despair-like changes in mice. J Neurosci 30:2571–2581
Kraft P, Yen Y-C, Stram DO, Morrison J (2007) Exploiting gene-environment interaction to detect genetic associations. Hum Hered 63:111–119
Laaris N, Haj-Dahmane S, Hamon M, Lanfumey L (1995) Glucocorticoid receptor-mediated inhibition by corticosterone of 5-HT1A autoreceptor functioning in the rat dorsal raphe nucleus. Neuropharmacology 34:1201–1210
Laaris N, Le Poul E, Hamon M, Lanfumey L (1997) Stress-induced alterations of somatodendritic 5-HT1A autoreceptor sensitivity in the rat dorsal raphe nucleus-in vitro electrophysiological evidence. Fundam Clin Pharmacol 11:206–214
Lanfumey L, Pardon MC, Laaris N, Joubert C, Hanoun N, Hamon M, Cohen-Salmon C (1999) 5-HT1A autoreceptor desensitization by chronic ultramild stress in mice. NeuroReport 10:3369–3374
Laucht M, Treutlein J, Blomeyer D, Buchmann AF, Schmid B, Becker K, Zimmermann US, Schmidt MH, Gn E, Rietschel M, Banaschewski T (2009) Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: evidence from a high-risk community sample of young adults. Int J Neuropsychopharmacol 12:737–747. doi:10.1017/S1461145708009875
Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531
Li Q, Wichems C, Heils A, Van De Kar LD, Lesch KP, Murphy DL (1999) Reduction of 5-hydroxytryptamine (5-HT)(1A)-mediated temperature and neuroendocrine responses and 5-HT(1A) binding sites in 5-HT transporter knock-out mice. J Pharmacol Exp Ther 291:999–1007
Li Q, Holmes A, Ma L, Van de Kar LD, Garcia F, Murphy DL (2004) Medial hypothalamic 5-hydroxytryptamine (5-HT)1A receptors regulate neuroendocrine responses to stress and exploratory locomotor activity: application of recombinant adenovirus containing 5-HT1A sequences. J Neurosci 24:10868–10877
Li X, Inoue T, Abekawa T, Weng S, Nakagawa S, Izumi T, Koyama T (2006) 5-HT1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5-HT1A receptors in the hippocampus and amygdala. Eur J Pharmacol 532:74–80
Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN (2003) Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 33:177–182
Luan JA, Wong MY, Wareham NJ (2001) Sample size determination for studies of gene-environment interaction. Int J Epidemiol 30:1035–1040
MacQueen GM, Ramakrishnan K, Ranasingan R, Chen B, Young LT (2003) Desipramine treatment reduces the long-term behavioral and neurochemical sequelae of early-life maternal separation. Int J Neuropsychopharmacol 6:391–396
Maercker A, Michael T, Fehm L, Becker ES, Margraf J (2004) Age of traumatisation as a predictor of post-traumatic stress disorder or major depression in young women. Br J Psychiatry 184:482–487. doi:10.1192/bjp.184.6.482
Marques AH, Silverman MN, Sternberg EM (2009) Glucocorticoid dysregulations and their clinical correlates. From receptors to therapeutics. Ann NY Acad Sci 1179:1–18
Mather K, Jinks JL (1982) Biometrical genetics: the study of continuous variation, 3rd edn. Chapman and Hall, London
McCart MR, Smith DW, Saunders BE, Kilpatrick DG, Resnick H, Ruggiero KJ (2007) Do urban adolescents become desensitized to community violence? Data from a national survey. Am J Orthopsychiatry 77:434–442
McCormick CM, Mathews IZ (2010) Adolescent development, hypothalamic-pituitary-adrenal function, and programming of adult learning and memory. Prog Neuro Psychopharmacol Biol Psychiatry 34:756–765
Mitchell SJ, Lewin A, Horn IB, Valentine D, Sanders-Phillips K, Joseph JG (2009) How does violence exposure affect the psychological health and parenting of young African-American mothers? Soc Sci Med 70:526–533
Moffit TE, Caspi A, Rutter M (2006) Measured gene-environment interactions in psychopathology: concepts, research strategies, and implications for research, intervention and public understanding of genetics. Perspect Psychol Sci 1:5–27
Moffitt TE, Caspi A, Rutter M (2005) Strategy for investigating interactions between measured genes and measured environments. Arch Gen Psychiatry 62:473–481
Monk C, McClure EB, Nelson EB, Zarahn E, Nilder RM, Leibenluft E, Charney DS, Ernst M, Pine DS (2003) Adolescent immaturity in attention-related brain engagement to emotional facial expressions. Neuroimage 20:420–428
Montag C, Weber B, Fliessbach K, Elger C, Reuter M (2009) The BDNF Val66Met polymorphism impacts parahippocampal and amygdala volume in healthy humans: incremental support for a genetic risk factor for depression. Psychol Med 39:1831–1839. doi:10.1017/S0033291709005509
Munafo MR, Flint J (2009) Replication and heterogeneity in gene–environment interaction studies. Int J Neuropsychopharmacol 12:727–729. doi:10.1017/S1461145709000479
Munafo MR, Durrant C, Lewis G, Flint J (2009) Gene–environment interactions at the serotonin transporter locus. Biol Psychiatry 65:211–219
Murgatroyd C, Wu Y, Bockmuhl Y, Spengler D (2010) Genes learn from stress: how infantile trauma programs us for depression. Epigenetics 5:194–199
Musazzi L, Mallei A, Tardito D, Gruber SH, El Khoury A, Racagni G, Mathe AA, Popoli M (2010) Early-life stress and antidepressant treatment involve synaptic signaling and Erk kinases in a gene-environment model of depression. J Psychiatr Res 44:511–520
Nakamura M, Ueno S, Sano A, Tanabe H (2000) The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry 5:32–38
Neale MC, Cardon LR (1992) Methodology for genetic studies of twins and families. Kluwer, Dordrecht
Nelson EC, Agrawal A, Pergadia ML, Lynskey MT, Todorov AA, Wang JC, Todd RD, Martin NG, Heath AC, Goate AM, Montgomery GW, Madden PA (2009) Association of childhood trauma exposure and GABRA2 polymorphisms with risk of posttraumatic stress disorder in adults. Mol Psychiatry 14:234–235
Nobile M, Rusconi M, Bellina M, Marino C, Giorda R, Carlet O, Vanzin L, Molteni M, Battaglia M (2009) The influence of family structure, the TPH2 G-703T and the 5-HTTLPR serotonergic genes upon affective problems in children aged 10–14 years. J Child Psychol Psychiatry 50(3):317–325
Nugent NR, Fyer A, Weissman M, Koenen KC (2010a) Genetics of anxiety disorders. In: Simpson HB, Neria Y, Lewis-Fernandez R, Schneier F (eds) Understanding anxiety: clinical and research perspectives from the Columbia University Department of Psychiatry. Cambridge University Press, New York, pp 139–155
Nugent NR, Amstadter AB, Koenen KC (2010b) Social support and interpersonal relationships following trauma. In: Horowitz LM, Strack S (eds) Handbook of interpersonal psychology: theory, research, assessment, and therapeutic interventions. Wiley, New York, pp 405–424
Paivio SC (2001) Stability of retrospective self-reports of child abuse and neglect before and after therapy for child abuse issues. Child Abuse Negl 25:1053–1068
Pariante CM, Lightman SL (2008) The HPA axis in major depression: classical theories and new developments. Trends Neurosci 31:464–468
Pehek EA, Nocjar C, Roth BL, Byrd TA, Mabrouk OS (2006) Evidence for the preferential involvement of 5-HT2A serotonin receptors in stress- and drug-induced dopamine release in the rat medial prefrontal cortex. Neuropsychopharmacology 31:265–277
Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR (2005) 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci 8:828–834
Plomin R, Davis OSP (2009) The future of genetics in psychology and psychiatry: microarrays, genome-wide association, and non-coding RNA. J Child Psychol Psychiatry 50:63–71
Plomin R, DeFries JC, Loehlin JC (1977) Genotype-environment interaction and correlation in the analysis of human behavior. Psychol Bull 84:309–322
Polanczyk G, Caspi A, Williams B, Price TS, Danese A, Sugden K, Uher R, Poulton R, Moffitt TE (2009) Protective effect of CRHR1 gene variants on the development of adult depression following childhood maltreatment: replication and extension. Arch Gen Psychiatry 66:978–985. doi:10.1001/archgenpsychiatry.2009.114
Preece MA, Dalley JW, Theobald DE, Robbins TW, Reynolds GP (2004) Region specific changes in forebrain 5-hydroxytryptamine1A and 5-hydroxytryptamine2A receptors in isolation-reared rats: an in vitro autoradiography study. Neuroscience 123:725–732
Raine A (2002) Biosocial studies of antisocial and violent behavior in children and adults: a review. J Abnorm Child Psychol 30:311–326
Raison CL, Miller AH (2003) When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry 160:1554–1565
Rao U, Hammen C, Daley SE (1999) Continuity of depression during the transition to adulthood: a 5-year longitudinal study of young women. J Am Acad Child Adolesc Psychiatry 38:908–915
Ressler KJ, Nemeroff (2000) Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 12:2–19
Ressler KJ, Bradley B, Mercer KB, Deveau TC, Smith AK, Gillespie CF, Nemeroff CB, Cubells JF, Binder EB (2010) Polymorphisms in CRHR1 and the serotonin transporter loci: gene × gene × environment interactions on depressive symptoms. Am J Med Genet B Neuropsychiatr Genet 153b:812–824. doi:10.1002/ajmg.b.31052
Risch N, Herrell R, Lehner T, Liang K-Y, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR (2009) Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 301:2462–2471. doi:10.1001/jama.2009.878
Ritchie K, Jaussent I, Stewart R, Dupuy A, Courtet P, Acelin M, Malafosse A (2009) Association of adverse chidhood environment and 5-HTTLPR genotype with late-life depression. J Clin Psychiatry 70:1281–1288
Roth S, Friedman MJ (1993) Prevalence and consequences of childhood trauma childhood trauma remembered: a report on the current scientific knowledge base and its applications. International society for traumatic stress studies. Northbrook, Illinois, pp 1–24
Rutter M (2008) Biological implications of gene–environment interaction. J Abnorm Child Psychol 36:969–975
Rutter M (2009) Gene-environment interactions: biologically valid pathway or artifact? Arch Gen Psychiatry 66:1287–1289
Rutter M (2010) Gene–environment interplay. Depress Anxiety 27:1–4
Rutter M, Kim-Cohen J, Maughan B (2006) Continuities and discontinuities in psychopathology between chidhood and adult life. J Child Psychol Psychiatry 47:276–295
Scaramella LV, Sohr-Preston SL, Callahan KL, Mirabile SP (2008) A test of the family stress model on toddler-aged children’s adjustment among hurricane katrina impacted and nonimpacted low-income families. J Clin Child Adolesc Psychol 37:530–541
Schule C, Zill P, Baghai TC, Eser D, Zwanzger P, Wenig N, Rupprecht R, Bondy B (2006) Brain-derived neurotrophic factor Val66Met polymorphism and dexamethasone/CRH test results in depressed patients. Psychoneuroendocrinology 31:1019–1025. doi:10.1016/j.psyneuen.2006.06.002
Silberg J, Pickles A, Rutter M, Hewitt J, Simonoff E, Maes H, Carbonneau R, Murrelle L, Foley D, Eaves L (1999) The influence of genetic factors and life stress on depression among adolescent girls. Arch Gen Psychiatry 56:225–232
Sjoberg RL, Nilsson KW, Nordquist N, Ohrvik J, Leppert J, Lindstrom L, Oreland L (2006) Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene. Int J Neuropsychopharmacol 9:443–449. doi:10.1017/S1461145705005936
Soliman F, Glatt CE, Bath KG, Levita L, Jones RM, Pattwell SS, Jing D, Tottenham N, Amso D, Somerville LH, Voss HU, Glover G, Ballon DJ, Liston C, Teslovich T, Van Kempen T, Lee FS, Casey BJ (2010) A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science 327:863–866
South SC, Krueger RF (2010) Genetic and environmental influences on internalizing psychopathology vary as a function of economic status. Psychol Med 41(1):107–117. doi:10.1017/S0033291710000279
Stein MB, Schork N, Gelernter J (2008) Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders. Neuropsychopharmacology 33:312–319
Surtees PG, Wainwright NW, Willis-Owen SA, Luben R, Day NE, Flint J (2006) Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder. Biol Psychiatry 59:224–229
Takase LF, Nogueira MI, Baratta M, Bland ST, Watkins LR, Maier SF, Fornal CA, Jacobs BL (2004) Inescapable shock activates serotonergic neurons in all raphe nuclei of rat. Behav Brain Res 153:233–239
Tambs K, Mourn T (1993) Low genetic effect and age-specific family effect for symptoms of anxiety and depression in nuclear families, halfsibs and twins. Journal of Affect Disorders 27:183–195
Taylor SE, Way BM, Welch WT, Hilmert CJ, Lehman BJ, Eisenberger NI (2006) Early family environment, current adversity, the serotonin transporter promoter polymorphism, and depressive symptomatology. Biol Psychiatry 60:671–676
Terr LC (1991) Childhood traumas: an outline and overview. Am J Psychiatry 148:10–20
Tjurmina OA, Armando I, Saavedra JM, Li Q, Murphy DL (2004) Life-long serotonin reuptake deficiency results in complex alterations in adrenomedullary responses to stress. Ann NY Acad Sci 1018:99–104
Tuvblad C, Grann M, Lichtenstein P (2006) Heritability for adolescent antisocial behavior differs with socioeconomic status: gene-environment interaction. J Child Psychol Psychiatry 47:734–743
Twitchell GR, Hanna GL, Cook EH, Stoltenberg SF, Fitzgerald HE, Zucker RA (2001) Serotonin transporter promoter polymorphism genotype is associated with behavioral disinhibition and negative effect in children of alcoholics. Alcohol Clin Exp Res 25:953–959
Tyrka AR, Carpenter LL, McDougle CJ, Kirwin PD, Owens MJ, Nemeroff CB, Strong DR, Price LH (2004) Increased CSF corticotropin-releasing factor during tryptophan depletion in healthy adults. Biol Psychiatry 56:531–534
Tyrka AR, Price LH, Gelernter J, Schepker C, Anderson GM, Carpenter LL (2009) Interaction of childhood maltreatment with the corticotropin-releasing hormone receptor gene: effects on hypothalamic-pituitary-adrenal axis reactivity. Biol Psychiatry 66:681–685
Uher R (2008) Gene-environment interaction: overcoming methodological challenges. Novartis Found Symp 293:13–26
Uher R, McGuffin P (2010) The moderation by the serotonin transporter gene of environmental adversity in the etiology of depression: 2009 update. Mol Psychiatry 15:18–22
Vinkers CH, Oosting RS, van Bogaert MJ, Olivier B, Groenink L (2010) Early-life blockade of 5-HT(1A) receptors alters adult anxiety behavior and benzodiazepine sensitivity. Biol Psychiatry 67:309–316
Wichers M, Kenis G, Jacobs N, Mengelers R, Derom C, Vlietinck R, van Os J (2008) The BDNF Va66Met × 5-HTTLPR × child adversity interaction and depressive symptoms: an attempt at replication. Am J Med Genet B Neuropsychiatr Genet 147B:120–123
Wust S, Federenko IS, van Rossum EF, Koper JW, Kumsta R, Entringer S, Hellhammer DH (2004a) A psychobiological perspective on genetic determinants of hypothalamus-pituitary-adrenal axis activity. Ann NY Acad Sci 1032:52–62
Wust S, Van Rossum EF, Federenko IS, Koper JW, Kumsta R, Hellhammer DH (2004b) Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychosocial stress. J Clin Endocrinol Metab 89:565–573
Xie P, Kranzler HR, Poling J, Stein MB, Anton RF, BradyRD, Farrer L, Gelernter J (2009) Interactive effect of stressful life events and the serotonin transporter 5-HTTLPR genotype on posttraumatic stress disorder diagnosis in 2 independent populations. Arch Gen Psychiatry 66:1201–1209. doi:10.1001/archgenpsychiatry.2009.153
Yehuda R, Flory JD, Pratchett LC, Buxbaum J, Ising M, Holsboer F (2010) Putative biological mechanisms for the association between early life adversity and the subsequent development of PTSD. Psychopharmacol Berl 212:405–417
Zinzow HM, Ruggiero KJ, Hanson RF, Smith DW, Saunders BE, Kilpatrick DG (2009) Witnessed community and parental violence in relation to substance use and delinquency in a national sample of adolescents. J Trauma Stress 22:525–533
Acknowledgment
Manuscript preparation was supported, in part, by NIMH grants K01 MH087240 (NRN), R01 MH083704 and Department of Defense grant PR064771 (ART), and NIMH grant R01 MH068767 (LLC).
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Nugent, N.R., Tyrka, A.R., Carpenter, L.L. et al. Gene–environment interactions: early life stress and risk for depressive and anxiety disorders. Psychopharmacology 214, 175–196 (2011). https://doi.org/10.1007/s00213-010-2151-x
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DOI: https://doi.org/10.1007/s00213-010-2151-x