Hostname: page-component-797576ffbb-lm8cj Total loading time: 0 Render date: 2023-12-08T03:12:07.394Z Has data issue: false Feature Flags: { "corePageComponentGetUserInfoFromSharedSession": true, "coreDisableEcommerce": false, "useRatesEcommerce": true } hasContentIssue false

Serotonin transporter linked polymorphic region (5-HTTLPR) genotype moderates the longitudinal impact of early caregiving on externalizing behavior

Published online by Cambridge University Press:  02 February 2015

Zoë H. Brett
Tulane University
Kathryn L. Humphreys
Tulane University
Anna T. Smyke
Tulane University
Mary Margaret Gleason
Tulane University
Charles A. Nelson
Harvard University Children's Hospital Boston
Charles H. Zeanah
Tulane University
Nathan A. Fox
University of Maryland
Stacy S. Drury*
Tulane University
Address correspondence and reprint requests to: Stacy S. Drury, Department of Psychiatry and Behavioral Sciences, 1430 Tulane Avenue, 8055, New Orleans, LA 70112; E-mail:


We examined caregiver report of externalizing behavior from 12 to 54 months of age in 102 children randomized to care as usual in institutions or to newly created high-quality foster care. At baseline no differences by group or genotype in externalizing were found. However, changes in externalizing from baseline to 42 months of age were moderated by the serotonin transporter linked polymorphic region genotype and intervention group, where the slope for short–short (S/S) individuals differed as a function of intervention group. The slope for individuals carrying the long allele did not significantly differ between groups. At 54 months of age, S/S children in the foster care group had the lowest levels of externalizing behavior, while children with the S/S genotype in the care as usual group demonstrated the highest rates of externalizing behavior. No intervention group differences were found in externalizing behavior among children who carried the long allele. These findings, within a randomized controlled trial of foster care compared to continued care as usual, indicate that the serotonin transporter linked polymorphic region genotype moderates the relation between early caregiving environments to predict externalizing behavior in children exposed to early institutional care in a manner most consistent with differential susceptibility.

Special Section Articles
Copyright © Cambridge University Press 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


Aguilera, M., Arias, B., Wichers, M., Barrantes-Vidal, N., Moya, J., Villa, H., et al. (2009). Early adversity and 5-HTT/BDNF genes: New evidence of Gene × Environment interactions on depressive symptoms in a general population. Psychological Medicine, 39, 14251432.Google Scholar
Aslund, C., Comasco, E., Nordquist, N., Leppert, J., Oreland, L., & Nilsson, K. (2013). Self-reported family socioeconomic status, the 5-HTTLPR genotype, and delinquent behavior in a community-based adolescent population. Aggressive Behavior, 39, 5263.Google Scholar
Auerbach, J., Faroy, M., Ebstein, R., Kahana, M., & Levine, J. (2001). The association of the dopamine D4 gene (DRD4) and the serotonin transporter promoter gene (5-HTTLPR) with temperament in 12-month-old infants. Journal of Child Psychology and Psychiatry, 42, 777783.Google Scholar
Bakermans-Kranenburg, M., & van IJzendoorn, M. (2011). Differential susceptibility to rearing environment depending on dopamine-related genes: New evidence and a meta-analysis. Development and Psychopathology, 23, 3952.Google Scholar
Bakermans-Kranenburg, M., van IJzendoorn, M., Mesman, J., Alink, L., & Juffer, F. (2008). Effects of an attachment-based intervention on daily cortisol moderated by dopamine receptor D4: A randomized control trial on 1- to 3-year-olds screened for externalizing behavior. Development and Psychopathology, 20, 805820.Google Scholar
Bakermans-Kranenburg, M., van IJzendoorn, M., Pijlman, F., Mesman, J., & Juffer, F. (2008). Experimental evidence for differential susceptibility: Dopamine D4 receptor polymorphism (DRD4 VNTR) moderates intervention effects on toddler' externalizing behavior in a randomized controlled trial. Development Psychology, 44, 293300.Google Scholar
Barr, C., Newman, T., Becker, M., Champoux, M., Lesch, K., Suomi, S., et al. (2003). Serotonin transporter gene variation is associated with alcohol sensitivity in rhesus macaques exposed to early-life stress. Alcoholism: Clinical and Experimental Research, 27, 812817.Google Scholar
Belsky, J., Bakermans-Kranenburg, M., & van IJzendoorn, M. (2007). For better and for worse: Differential susceptibility to environmental influences. Current Directions in Psychological Science, 16, 300304.Google Scholar
Belsky, J., & Beaver, K. (2011). Cumulative-genetic plasticity, parenting and adolescent self-regulation. Journal of Child Psychology and Psychiatry, 5, 619626.Google Scholar
Belsky, J., Hsieh, K., & Crnic, K. (1998). Mothering, fathering, and infant negativity as antecedents of boys' externalizing problems and inhibition at age 3 years: Differential susceptibility to rearing experience? Development and Psychopathology, 10, 301319.Google Scholar
Belsky, J., Jonassaint, C., Pleuss, M., Stanton, M., Brummet, B., & Williams, R. (2009). Vulnerability genes or plasticity genes? Molecular Psychiatry, 14, 746754.Google Scholar
Belsky, J., & Pleuss, M. (2013). Beyond risk, resilience, and dysregulation: Phenotypic plasticity and human development. Development and Psychopathology, 25, 12431261.Google Scholar
Belsky, J., Pluess, M., & Pleuss, M. (2009). Beyond diathesis stress: Differential susceptibility to environmental influences. Psychological Bulletin, 135, 885908.Google Scholar
Belsky, J., Pluess, M., & Widaman, K. (2013). Confirmatory and competitive evaluation of alternative gene–environment interaction hypotheses. Journal of Child Psychology and Psychiatry, 54, 11351143.Google Scholar
Bogdan, R., Agrawal, A., Gaffrey, M., Tillman, R., & Luby, J. (2014). Serotonin transporter-linked polymorphic region (5-HTTLPR) genotype and stressful life events interact to predict preschool-onset depression: A replication and developmental extension. Journal of Child Psychology and Psychiatry, 55, 448457.Google Scholar
Bos, K., Fox, N., Zeanah, C., & Nelson, C. (2009). Effects of early psychosocial deprivation on the development of memory and executive function. Frontiers in Behavioral Neuroscience, 3, 17.Google Scholar
Bradley, R. H., & Corwyn, R. F. (2008). Infant temperament, parenting, and externalizing behavior in first grade: A test of the differential susceptibility hypothesis. Journal of Child Psychology and Psychiatry, 49, 124131.Google Scholar
Brody, G., Beach, S., Philibert, R., Chen, Y., & Murry, V. (2009). Prevention effects moderate the association of 5-HTTLPR and youth risk behavior initiation: Gene × Environment hypotheses tested via a randomized prevention design. Child Development, 80, 645661.Google Scholar
Cadoret, R., Langbehn, D., Caspers, K., Troughton, E., Yucuis, R., Sandhu, H., et al. (2003). Associations of the serotonin transporter promoter polymorphim with aggressivity, attention deficit, and conduct disorder in an adoptee population. Comprehensive Psychiatry, 44, 88101.Google Scholar
Canli, T., & Lesch, K. (2007). Long story short: The serotonin transporter in emotion regulation and social cognition. Nature Neuroscience, 10, 11031108.Google Scholar
Carter, A., Briggs-Gowan, M., Jones, S., & Little, T. (2003). The Infant–Toddler Social and Emotional Assessment (ITSEA): Factor structure, reliability, and validity. Journal of Abnormal Child Psychology, 31, 495514.Google Scholar
Champoux, M., Bennett, A., Shannon, C., Higley, J., Lesch, K., & Suomi, S. (2002). Serotonin transporter gene polymorphism, differential early rearing, and behavior in rhesus monkey neonates. Molecular Psychiatry, 7, 10581063.Google Scholar
Cicchetti, D. (2013). Annual Research Review: Resilient functioning in maltreated children—Past, present, and future perspectives. Journal of Child Psychology and Psychiatry, 54, 402422.Google Scholar
Cicchetti, D., & Rogosch, F. (2012). Gene × Environment interaction and resilience: Effects of child maltreatment and serotonin, corticotropin releasing hormone, dopamine, and oxytocin genes. Development and Psychopathology, 24, 411427.Google Scholar
Davies, D., & Cicchetti, D. (2013). How and why does the 5-HTTLPR gene moderate associations between maternal unresponsiveness and children's disruptive problems? Child Development. Advance online publication.Google Scholar
Douglas, K., Chan, G., Gelernter, J., Arias, A., Anton, R., Poling, J., et al. (2011). 5-HTTLPR as a potential moderator of the effects of adverse childhood experiences on risk of antisocial personality disorder. Psychiatric Genetics, 21, 240248.Google Scholar
Drury, S., Gleason, M., Theall, K., Smyke, A., Nelson, C., Fox, N., et al. (2012). Genetic sensitivity to the caregiving context: The influence of 5-HTTLPR and BDNF val66met on indiscriminate social behavior. Physiology & Behavior, 106, 728735.Google Scholar
Drury, S., Theall, K., Smyke, A., Keats, B., Egger, H., Nelson, C., et al. (2010). Modification of depression by COMT val158met polymorphism in children exposed to early severe psychosocial deprivation. Child Abuse and Neglect, 34, 387395.Google Scholar
Egger, H., Erkanli, A., Keeler, G., Potts, E., Walter, B., & Angold, A. (2006). Test–retest reliability of the Preschool Age Psychiatric Assessment (PAPA). Journal of the American Academy of Child & Adolescent Psychiatry, 45, 538549.Google Scholar
Ellis, B., Boyce, W., Belsky, J., Bakermans-Kranenburg, M., & van IJzendoorn, M. (2011). Differential susceptibility to the environment: An evolutionary–neurodevelopmental theory. Development and Psychopathology, 23, 728.Google Scholar
Fox, N., Almas, A., Degnan, K., Nelson, C., & Zeanah, C. (2011). The effects of severe psychosocial deprivation and foster care intervention on cognitive development at 8 years of age: Findings from the Bucharest Early Intervention Project. Journal of Child Psychology and Psychiatry, 52, 919928.Google Scholar
Gilliom, M., & Shaw, D. (2004). Codevelopment of externalizing and internalizing problems in early childhood. Development and Psychopathology, 16, 313333.Google Scholar
Gunnar, M. R., Wenner, J. A., Thomas, K. M., Glatt, C. E., Mckenna, M. C., & Clark, A. G. (2012). The brain-derived neurotrophic factor Val66Met polymorphism moderates early deprivation effects on attention problems. Development and Psychopathology, 24, 12151223.Google Scholar
Hankin, B. L., Nederhof, E., Oppenheimer, C. W., Jenness, J., Young, J. F., Abela, J. R. Z., et al. (2011). Differential susceptibility in youth: Evidence that 5-HTTLPR × Positive Parenting is associated with positive affect “for better and worse.” Translational Psychiatry, 1, e44.Google Scholar
Hariri, A., & Holmes, A. (2006). Genetics of emotional regulation: The role of the serotonin transporter in neural function. Trends in Cognitive Science, 10, 182191.Google Scholar
Homberg, J., & Lesch, K. (2011). Looking on the bright side of serotonin transporter gene variation. Biological Psychiatry, 69, 513519.Google Scholar
Humphreys, K., Scheeringa, M. S., & Drury, S. (2014). Race moderates the association between COMT genotype and PTSD in preschool children. Journal of Child and Adolescent Psychopharmacology, 24, 454457.Google Scholar
Hutchison, K., Stallings, M., McGeary, J., & Bryan, A. (2004). Population stratification in the candidate gene study: Fatal threat or red herring? Psychological Bulletin, 130, 6679.Google Scholar
Johnson, D., Guthrie, D., Smyke, A., Koga, S., Fox, N., Zeanah, C., et al. (2010). Growth and associations between auxology, caregiving environment, and cognition in social deprived Romanian children randomized to foster vs ongoing institutional care. Archives of Pediatric Adolescent Medicine, 164, 507516.Google Scholar
Karg, K., Burmeister, M., Shedden, K., & Sen, S. (2011). The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Archives of General Psychiatry, 68, 444454.Google Scholar
Kegel, C., Bus, A., & van IJzendoorn, M. (2011). Differential susceptibility in early literacy instruction through computer games: The role of the dopamine D4 receptor gene (DRD4). Mind, Brain, and Education, 5, 7178.Google Scholar
Kendler, K. S., Gardner, C., & Prescott, C. (2003). Personality and the experience of environmental adversity. Psychological Medicine, 33, 11931202.Google Scholar
Knafo, A., Israel, S., & Ebstein, R. P. (2011). Heritability of children's prosocial behavior and differential susceptibility to parenting by variation in the dopamine receptor D4 gene. Development and Psychopathology, 23, 5367.Google Scholar
Kreek, M., Nielsen, D., & LaForge, K. (2005). Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nature Neuroscience, 8, 14501457.Google Scholar
Kreppner, J., O'Connor, T., & Rutter, M. (2001). The English and Romanian Adoptees Study Team: Can inattention/overactivity be an institutional deprivation syndrome? Journal of Abnormal Child Psychology, 29, 513528.Google Scholar
Kumsta, R., Stevens, S., Brookes, K., Schlotz, W., Castle, J., Beckett, C., et al. (2010). 5HTT genotype moderates the influence of early institutional deprivation on emotional problems in adolescence: Evidence from and English and Romanian Adoptee (ERA) study. Journal of Child Psychology and Psychiatry, 51, 755762.Google Scholar
Lavigne, J., Gibbons, R., Christoffel, K., Arend, R., Rosenbaum, D., Binns, H., et al. (1996). Prevalence rates and correlates of psychiatric disorders among preschool children. Journal of the American Academy of Child & Adolescent Psychiatry, 35, 204214.Google Scholar
Lesch, K., Balling, U., Gross, J., Strauss, K., Wolozin, B., Murphy, D., et al. (1994). Organization of the human serotonin transporter gene. Journal of Neurologic Transmission, 95, 157162.Google Scholar
Manuck, S., Flory, J., Ferrell, R., & Muldoon, M. (2004). Socio-economic status covaries with central nervous system serotonergic responsivity as a function of allelic variation in the serotonin transporter gene-linked polymorphic region. Psychoneuroendocrinilogy, 29, 651668.Google Scholar
Millum, J., & Emanuel, E. (2007). The ethics of international research with abandoned children. Science, 318, 18741875.Google Scholar
Nakamura, M., Ueno, S., Sano, A., & Tanabe, H. (2000). The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Molecular Psychiatry, 5, 3238.Google Scholar
Nederhof, E., Bouma, E. M. C., Riese, H., Laceulle, O. M., Ormel, J., & Oldehinkel, A. J. (2010). Evidence for plasticity genotypes in a gene–gene–environment interaction: The TRAILS study. Genes, Brain, and Behavior, 9, 968973.Google Scholar
Nelson, C., Fox, N., & Zeanah, C. (2014). Romania's abandoned children: Deprivation, brain development and the struggle for recovery. Cambridge, MA: Harvard University Press.Google Scholar
Nelson, C., Zeanah, C., Fox, N., Marshall, P., Smyke, A., & Guthrie, D. (2007). Cognitive recovery in socially deprived young children: The Bucharest Early Intervention Project. Science, 318, 19371940.Google Scholar
Nobile, M., Giorda, R., Marino, C., Carlet, O., Pastore, V., Vanzin, L., et al. (2007). Socioeconomic status mediates the genetic contribution of the dopamine receptor D4 and serotonin transporter linked promoter region repeat polymorphisms to externalization in preadolescence. Development and Psychopathology, 19, 11471160.Google Scholar
Owens, M., Goodyer, I. M., Wilkinson, P., Bhardwaj, A., Abbott, R., Croudace, T., et al. (2012). 5-HTTLPR and early childhood adversities moderate cognitive and emotional processing in adolescence. PLOS ONE, 7, e48482.Google Scholar
Philibert, R. A., Sandhu, H., Hollenbeck, N., Gunter, T., Adams, W., & Madan, A. (2008). The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. American Journal of Medical Genetics, 147B, 543549.Google Scholar
Roisman, G., Newman, D., Fraley, R., Haltigan, J., Groh, A., & Haydon, K. (2012). Distinguishing differential susceptibility from diathesis–stress: Recommendations for evaluating interaction effects. Development and Psychopathology, 24, 389409.Google Scholar
Rutter, M., Beckett, C., Castle, J., Colvert, E., Kreppner, J., Mehta, M., et al. (2007). Effects of profound early institutional deprivation: An overview of findings from a UK longitudinal study of Romanian adoptees. European Journal of Developmental Psychology, 4, 332350.Google Scholar
Rutter, M., Dunn, J., Plomin, R., Simonoff, E., Pickles, A., Maughan, B., et al. (1997). Integrating nature and nurture: Implications of person–environment correlations and interactions for developmental psychopathology. Development and Psychopathology, 9, 335364.Google Scholar
Shaw, D., Owens, E., Giovannelli, J., & Winslow, E. (2001). Infant and toddler pathways leading to early externalizing disorders. Journal of the American Academy of Child & Adolescent Psychiatry, 40, 3643.Google Scholar
Sheridan, M., Drury, S., McLaughlin, K., & Almas, A. (2010). Early institutionalization: Neurobiological consequences and genetic modifiers. Neuropsychology Reviews, 20, 414429.Google Scholar
Sheridan, M., Fox, N., Zeanah, C., McLaughlin, K., & Nelson, C. (2012). Variation in neural development as a result of exposure to institutionalization early in childhood. Proceedings of the National Academy of Sciences, 109, 1292712932.Google Scholar
Simons, R. L., Lei, M. K., Beach, S. R. H., Brody, G. H., Philibert, R. A., & Gibbons, F. X. (2011). Social environmental variation, plasticity genes, and aggression: Evidence for the differential susceptibility hypothesis. American Sociological Review, 76, 833912.Google Scholar
Simons, R. L., Lei, M. K., Stewart, E. A., Beach, S. R. H., Brody, G. H., Philibert, R. A., et al. (2012). Social adversity, genetic variation, street code, and aggression: A genetically informed model of violent behavior. Youth Violence and Juvenile Justice, 10, 324.Google Scholar
Smyke, A., Koga, S., Johnson, D., Fox, N., Marshall, P., Nelson, C., et al. (2007). The caregiving context in institution reared and family reared infants and toddlers in Romania. Journal of Child Psychology and Psychiatry, 48, 210218.Google Scholar
Sonuga-Barke, E., Oades, R., Psychogiou, L., Chen, W., Franke, B., Buitelaar, J., et al. (2009). Dopamine and serotonin transporter genotypes moderated sensitivity to maternal expressed emotion: The case of conduct and emotional problems in attention deficit/hyperactivity disorder. Journal of Child Psychology and Psychiatry, 50, 10521063.Google Scholar
Sturge-Apple, M., Davies, P., Martin, M., Cicchetti, D., & Hentges, R. (2012). An examination of the impact of harsh parenting contexts on children's adaptation within an evolutionary framework. Developmental Psychology, 48, 791805.Google Scholar
Sulik, M., Eisenberg, N., Lemery-Chalfant, K., Spinrad, T., Silva, K., Eggum, N., et al. (2012). Interactions between serotonin transporter gene haplotypes and quality of mothers' parenting predict the development of children's noncompliance. Developmental Psychology, 48, 740754.Google Scholar
Suomi, S. (2004). How gene–environment interactions shape biobehavioral development: Lessons from the study of rhesus monkes. Research in Human Development, 1, 205222.Google Scholar
Uher, R., & McGuffin, P. (2008). The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: Review and methodological analysis. Molecular Psychiatry, 13, 131146.Google Scholar
Vanderwert, R., Marshall, P., Nelson, C., Zeanah, C., & Fox, N. (2010). Timing of intervention affects brain electrical activity in children exposed to severe psychosocial neglect. PLOS ONE, 5, e11415.Google Scholar
van Goozen, S., Fairchild, G., Snoek, H., & Harold, G. (2007). The evidence for a neurobiological model of childhood antisocial behavior. Psychological Bulletin, 133, 149182.Google Scholar
van IJzendoorn, M., & Bakermans-Kranenburg, M. (2012). Differential susceptibility experiments: Going beyond correlational evidence—Comment on beyond mental health, differential susceptibility articles. Developmental Psychology, 48, 769774.Google Scholar
van IJzendoorn, M., Bakermans-Kranenburg, M., Belsky, J., Beach, S., Brody, G., Dodge, K., et al. (2011). Gene by environment experiments: A new approach to finding the missing heritability. Nature Reviews Genetics, 12, 881.Google Scholar
van IJzendoorn, M., Belsky, J., & Bakermans-Kranenburg, M. (2012). Serotonin transporter genotype 5-HTTLPR as a marker of differential susceptibility? A meta-analysis of child and adolescent gene-by-environment studies. Translational Psychiatry, 2, e147.Google Scholar
van Ijzendoorn, M., Caspers, K., Bakermans-Kranenburg, M., Beach, S., & Philibert, R. (2010). Methylation matters: Interaction between methylation density and serotonin transporter genotype predicts unresolved loss or trauma. Biological Psychiatry, 68, 405407.Google Scholar
Vaske, J., Newsome, J., & Wright, J. P. (2012). Interaction of serotonin transporter linked polymorphic region and childhood neglect on criminal behavior and substance use for males and females. Development and Psychopathology, 24, 181193.Google Scholar
Wichers, M., Kenis, G., Jacobs, N., Mengelers, R., Derom, C., Vietnick, R., et al. (2008). The BDNF val(66)met × 5-HTTLPR × Child Adversity interaction on depressive symptoms: An attempt at replication. American Journal of Medical Genetics, 147B, 120123.Google Scholar
Yonan, A., Palmer, A., & Gillian, T. (2006). Hardy–Weinberg disequilibrium identified genotyping error of the serotonin transporter (SLC6a4) promoter polymorphism. Psychiatric Genetics, 16, 3134.Google Scholar
Zeanah, C. (2007). Reactive attachment disorder. In Narrow, W., First, M., Sirovatka, P., & Regier, D. (Eds.), Age and gender considerations in psychiatric diagnosis: A research agenda for the DSM-V. Arlington, VA: APA Press.Google Scholar
Zeanah, C., Egger, H., Smyke, A., Nelson, C., Fox, N., Marshall, P., et al. (2009). Institutional rearing and psychiatric disorders in Romanian preschool children. American Journal of Psychiatry, 166, 777785.Google Scholar
Zeanah, C., Fox, N., & Nelson, C. (2012). The Bucharest Early Intervention Project: Case study in the ethics of mental health research. Journal of Nervous and Mental Diseases, 200, 243247.Google Scholar
Zeanah, C., Nelson, C., Fox, N., Smyke, A., Marshall, P., Parker, S., et al. (2003). Designing research to study the effects of institutionalization on brain and behavioral development: The Bucharest Early Intervention Project. Development and Psychopathology, 15, 885907.Google Scholar
Zimmermann, P., Mohr, C., & Spangler, G. (2009). Genetic and attachment influences on adolescents' regulation of autonomy and aggressiveness. Journal of Child Psychology and Psychiatry, 50, 13391347.Google Scholar