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Interaction between prenatal stress and dopamine D4 receptor genotype in predicting aggression and cortisol levels in young adults

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Abstract

Rationale

Considerable evidence suggests that genetic factors combine with environmental influences to impact on the development of aggressive behavior. A genetic variant that has repeatedly been reported to render individuals more sensitive to the presence of adverse experiences, including stress exposure during fetal life, is the seven-repeat allele of the dopamine D4 receptor (DRD4) gene.

Objectives

The present investigation concentrated on the interplay of prenatal maternal stress and DRD4 genotype in predicting self-reported aggression in young adults. As disruption of the hypothalamic-pituitary-adrenal system has been discussed as a pathophysiological pathway to aggression, cortisol stress reactivity was additionally examined.

Methods

As part of an epidemiological cohort study, prenatal maternal stress was assessed by maternal interview 3 months after childbirth. Between the ages of 19 and 23 years, 298 offspring (140 males, 158 females) completed the Young Adult Self-Report to measure aggressive behavior and were genotyped for the DRD4 gene. At 19 years, 219 participants additionally underwent the Trier Social Stress Test to determine cortisol reactivity.

Results

Extending earlier findings with respect to childhood antisocial behavior, the results revealed that, under conditions of higher prenatal maternal stress, carriers of the DRD4 seven-repeat allele displayed more aggression in adulthood (p = 0.032). Moreover, the same conditions which seemed to promote aggression were found to predict attenuated cortisol secretion (p = 0.028).

Conclusions

This is the first study to indicate a long-term impact of prenatal stress exposure on the cortisol stress response depending on DRD4 genotype.

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References

  • Achenbach T (1991) Young Adult Self Report. Department of Psychiatry, University of Vermont, Burlington, VT

    Google Scholar 

  • Agrez U, Winkler Metzke C, Steinhausen H-C (2011) Psychometric characteristics of the German version of the Young Adult Self-Report (YASR). Z Klin Psychol Psychother 40:75–84

    Article  Google Scholar 

  • Alink LR, van Ijzendoorn MH, Bakermans-Kranenburg MJ, Mesman J, Juffer F, Koot HM (2008) Cortisol and externalizing behavior in children and adolescents: mixed meta-analytic evidence for the inverse relation of basal cortisol and cortisol reactivity with externalizing behavior. Dev Psychobiol 50:427–450

    Article  CAS  PubMed  Google Scholar 

  • Asghari V, Schoots O, van Kats S, Ohara K, Jovanovic V, Guan HC, Bunzow JR, Petronis A, Van Tol HH (1994) Dopamine D4 receptor repeat: analysis of different native and mutant forms of the human and rat genes. Mol Pharmacol 46:364–373

    CAS  PubMed  Google Scholar 

  • Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH (1995) Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J Neurochem 65:1157–1165

    Article  CAS  PubMed  Google Scholar 

  • Bakermans-Kranenburg MJ, van Ijzendoorn MH (2006) Gene-environment interaction of the dopamine D4 receptor (DRD4) and observed maternal insensitivity predicting externalizing behavior in preschoolers. Dev Psychobiol 48:406–409

    Article  CAS  PubMed  Google Scholar 

  • Bakermans-Kranenburg MJ, van Ijzendoorn MH (2011) Differential susceptibility to rearing environment depending on dopamine-related genes: new evidence and a meta-analysis. Dev Psychopathol 23:39–52

    Article  PubMed  Google Scholar 

  • Bakermans-Kranenburg MJ, van Ijzendoorn MH, Pijlman FT, Mesman J, Juffer F (2008) Experimental evidence for differential susceptibility: dopamine D4 receptor polymorphism (DRD4 VNTR) moderates intervention effects on toddlers’ externalizing behavior in a randomized controlled trial. Dev Psychol 44:293–300

    Article  PubMed  Google Scholar 

  • Barker ED, Maughan B (2009) Differentiating early-onset persistent versus childhood-limited conduct problem youth. Am J Psychiatry 166:900–908

    Article  PubMed  Google Scholar 

  • Beach SR, Lei MK, Brody GH, Simons RL, Cutrona C, Philibert RA (2012) Genetic moderation of contextual effects on negative arousal and parenting in African-American parents. J Fam Psychol 26:46–55

    Article  PubMed Central  PubMed  Google Scholar 

  • Berry D, Deater-Deckard K, McCartney K, Wang Z, Petrill SA (2013) Gene-environment interaction between dopamine receptor D4 7-repeat polymorphism and early maternal sensitivity predicts inattention trajectories across middle childhood. Dev Psychopathol 25:291–306

    Article  PubMed  Google Scholar 

  • Brennan PA, Pargas R, Walker EF, Green P, Newport DJ, Stowe Z (2008) Maternal depression and infant cortisol: influences of timing, comorbidity and treatment. J Child Psychol Psychiatry 49:1099–1107

    Article  PubMed Central  PubMed  Google Scholar 

  • Cottrell EC, Seckl JR (2009) Prenatal stress, glucocorticoids and the programming of adult disease. Front Behav Neurosci 3:19

    Article  PubMed Central  PubMed  Google Scholar 

  • Dilalla LF, Gheyara S, Bersted K (2013) The Southern Illinois Twins and Siblings Study (SITSS): description and update. Twin Res Hum Genet 16:371–375

    Article  PubMed  Google Scholar 

  • Ding YC, Chi HC, Grady DL, Morishima A, Kidd JR, Kidd KK, Flodman P, Spence MA, Schuck S, Swanson JM, Zhang YP, Moyzis RK (2002) Evidence of positive selection acting at the human dopamine receptor D4 gene locus. Proc Natl Acad Sci U S A 99:309–314

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Docherty SJ, Davis OS, Haworth CM, Plomin R, D’Souza U, Mill J (2012) A genetic association study of DNA methylation levels in the DRD4 gene region finds associations with nearby SNPs. Behav Brain Funct 8:31

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Entringer S, Kumsta R, Hellhammer DH, Wadhwa PD, Wust S (2009) Prenatal exposure to maternal psychosocial stress and HPA axis regulation in young adults. Horm Behav 55:292–298

    Article  CAS  PubMed  Google Scholar 

  • Esser G, Blanz B, Geisel B, Laucht M (1989) Mannheim Parent Interview—structured interview for child psychiatric disorders. Beltz, Weinheim

    Google Scholar 

  • Fergusson DM, Boden JM, Horwood LJ, Miller AL, Kennedy MA (2011) MAOA, abuse exposure and antisocial behaviour: 30-year longitudinal study. Br J Psychiatry 198:457–463

    Article  PubMed Central  PubMed  Google Scholar 

  • Field T, Diego M (2008) Cortisol: the culprit prenatal stress variable. Int J Neurosci 118:1181

    Article  CAS  PubMed  Google Scholar 

  • Glover V, O’Connor TG, O’Donnell K (2010) Prenatal stress and the programming of the HPA axis. Neurosci Biobehav Rev 35:17–22

    Article  CAS  PubMed  Google Scholar 

  • Gowin JL, Green CE, Alcorn JL III, Swann AC, Moeller FG, Lane SD (2013) The role of cortisol and psychopathy in the cycle of violence. Psychopharmacology (Berlin) 227:661–672

    Article  CAS  Google Scholar 

  • Grizenko N, Fortier ME, Zadorozny C, Thakur G, Schmitz N, Duval R, Joober R (2012) Maternal stress during pregnancy, ADHD symptomatology in children and genotype: gene-environment interaction. J Can Acad Child Adolesc Psychiatry 21:9–15

    PubMed Central  PubMed  Google Scholar 

  • Hawes DJ, Brennan J, Dadds MR (2009) Cortisol, callous-unemotional traits, and pathways to antisocial behavior. Curr Opin Psychiatry 22:357–362

    Article  PubMed  Google Scholar 

  • Hay DF, Pawlby S, Waters CS, Perra O, Sharp D (2010) Mothers’ antenatal depression and their children’s antisocial outcomes. Child Dev 81:149–165

    Article  PubMed  Google Scholar 

  • Hensleigh E, Pritchard LM (2013) Glucocorticoid receptor expression and sub-cellular localization in dopamine neurons of the rat midbrain. Neurosci Lett. doi: 10.1016/j.neulet.2013.09.067

  • Huizink AC, Bartels M, Rose RJ, Pulkkinen L, Eriksson CJ, Kaprio J (2008) Chernobyl exposure as stressor during pregnancy and hormone levels in adolescent offspring. J Epidemiol Community Health 62:e5

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jaffee SR, Strait LB, Odgers CL (2012) From correlates to causes: can quasi-experimental studies and statistical innovations bring us closer to identifying the causes of antisocial behavior? Psychol Bull 138:272–295

    Article  PubMed Central  PubMed  Google Scholar 

  • Kazmi MA, Snyder LA, Cypess AM, Graber SG, Sakmar TP (2000) Selective reconstitution of human D4 dopamine receptor variants with Gi alpha subtypes. Biochemistry 39:3734–3744

    Article  CAS  PubMed  Google Scholar 

  • Kirschbaum C, Pirke KM, Hellhammer DH (1993) The ‘Trier Social Stress Test’—a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology 28:76–81

    Article  CAS  PubMed  Google Scholar 

  • Klengel T, Binder EB (2013) Allele-specific epigenetic modification: a molecular mechanism for gene-environment interactions in stress-related psychiatric disorders? Epigenomics 5:109–112

    Article  CAS  PubMed  Google Scholar 

  • Kudielka BM, Wüst S, Kirschbaum C, Hellhammer DH (2007) Trier Social Stress Test. In: Fink G (ed) Encyclopedia of stress. Academic Press, Oxford, pp 776–781

    Chapter  Google Scholar 

  • Langley K, Turic D, Rice F, Holmans P, van den Bree MB, Craddock N, Kent L, Owen MJ, O’Donovan MC, Thapar A (2008) Testing for gene × environment interaction effects in attention deficit hyperactivity disorder and associated antisocial behavior. Am J Med Genet B Neuropsychiatr Genet 147B:49–53

    Article  CAS  PubMed  Google Scholar 

  • Laucht M, Esser G, Schmidt MH (1997) Developmental outcome of infants born with biological and psychosocial risks. J Child Psychol Psychiatry 38:843–853

    Article  CAS  PubMed  Google Scholar 

  • Laucht M, Esser G, Baving L, Gerhold M, Hoesch I, Ihle W, Steigleider P, Stock B, Stoehr RM, Weindrich D, Schmidt MH (2000) Behavioral sequelae of perinatal insults and early family adversity at 8 years of age. J Am Acad Child Adolesc Psychiatry 39:1229–1237

    Article  CAS  PubMed  Google Scholar 

  • Lichter JB, Barr CL, Kennedy JL, Van Tol HH, Kidd KK, Livak KJ (1993) A hypervariable segment in the human dopamine receptor D4 (DRD4) gene. Hum Mol Genet 2:767–773

    Article  CAS  PubMed  Google Scholar 

  • Maki P, Veijola J, Rasanen P, Joukamaa M, Valonen P, Jokelainen J, Isohanni M (2003) Criminality in the offspring of antenatally depressed mothers: a 33-year follow-up of the Northern Finland 1966 Birth Cohort. J Affect Disord 74:273–278

    Article  PubMed  Google Scholar 

  • Meaney MJ (2001) Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu Rev Neurosci 24:1161–1192

    Article  CAS  PubMed  Google Scholar 

  • Müller R, Abbet JP (1991) Changing trends in the consumption of legal and illegal drugs by 11–16-year-old adolescent pupils. Findings from a study conducted under the auspices of the WHO Europe. Swiss Professional Service for Alcohol Problems, Lausanne

    Google Scholar 

  • Nederhof E, Belsky J, Ormel J, Oldehinkel AJ (2012) Effects of divorce on Dutch boys’ and girls’ externalizing behavior in gene × environment perspective: diathesis stress or differential susceptibility in the Dutch Tracking Adolescents’ Individual Lives Survey study? Dev Psychopathol 24:929–939

    Article  PubMed  Google Scholar 

  • Nobile M, Giorda R, Marino C, Carlet O, Pastore V, Vanzin L, Bellina M, Molteni M, Battaglia M (2007) Socioeconomic status mediates the genetic contribution of the dopamine receptor D4 and serotonin transporter linked promoter region repeat polymorphisms to externalization in preadolescence. Dev Psychopathol 19:1147–1160

    PubMed  Google Scholar 

  • Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM (2008) Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 3:97–106

    Article  PubMed  Google Scholar 

  • O’Connor TG, Heron J, Golding J, Beveridge M, Glover V (2002) Maternal antenatal anxiety and children’s behavioural/emotional problems at 4 years. Report from the Avon Longitudinal Study of Parents and Children. Br J Psychiatry 180:502–508

    Article  PubMed  Google Scholar 

  • O’Connor TG, Heron J, Golding J, Glover V (2003) Maternal antenatal anxiety and behavioural/emotional problems in children: a test of a programming hypothesis. J Child Psychol Psychiatry 44:1025–1036

    Article  PubMed  Google Scholar 

  • O’Donnell KJ, Bugge JA, Freeman L, Khalife N, O’Connor TG, Glover V (2012) Maternal prenatal anxiety and downregulation of placental 11beta-HSD2. Psychoneuroendocrinology 37:818–826

    Article  PubMed  Google Scholar 

  • O’Donnell KJ, Glover V, Jenkins J, Browne D, Ben-Shlomo Y, Golding J, O’Connor TG (2013) Prenatal maternal mood is associated with altered diurnal cortisol in adolescence. Psychoneuroendocrinology 38:1630–1638

    Article  PubMed  Google Scholar 

  • Platje E, Jansen LM, Raine A, Branje SJ, Doreleijers TA, de Vries-Bouw M, Popma A, van Lier PA, Koot HM, Meeus WH, Vermeiren RR (2013) Longitudinal associations in adolescence between cortisol and persistent aggressive or rule-breaking behavior. Biol Psychol 93:132–137

    Article  PubMed  Google Scholar 

  • Popma A, Vermeiren R, Geluk CA, Rinne T, van den Brink W, Knol DL, Jansen LM, van Engeland H, Doreleijers TA (2007) Cortisol moderates the relationship between testosterone and aggression in delinquent male adolescents. Biol Psychiatry 61:405–411

    Article  CAS  PubMed  Google Scholar 

  • Poustka L, Maras A, Hohm E, Fellinger J, Holtmann M, Banaschewski T, Lewicka S, Schmidt MH, Esser G, Laucht M (2010) Negative association between plasma cortisol levels and aggression in a high-risk community sample of adolescents. J Neural Transm 117:621–627

    Article  CAS  PubMed  Google Scholar 

  • Rutter M, Quinton D (1977) Psychiatric disorder—ecological factors and concepts of causation. In: McGurk M (ed) Ecological factors in human development. North Holland, Amsterdam, pp 173–187

    Google Scholar 

  • Seckl JR, Holmes MC (2007) Mechanisms of disease: glucocorticoids, their placental metabolism and fetal ‘programming’ of adult pathophysiology. Nat Clin Pract Endocrinol Metab 3:479–488

    Article  CAS  PubMed  Google Scholar 

  • Turic D, Swanson J, Sonuga-Barke E (2010) DRD4 and DAT1 in ADHD: functional neurobiology to pharmacogenetics. Pharmgenomics Pers Med 3:61–78

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tuvblad C, Baker LA (2011) Human aggression across the lifespan: genetic propensities and environmental moderators. Adv Genet 75:171–214

    Article  PubMed Central  PubMed  Google Scholar 

  • Urizar GG Jr, Munoz RF (2011) Impact of a prenatal cognitive-behavioral stress management intervention on salivary cortisol levels in low-income mothers and their infants. Psychoneuroendocrinology 36:1480–1494

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Witt SH, Buchmann AF, Blomeyer D, Nieratschker V, Treutlein J, Esser G, Schmidt MH, Bidlingmaier M, Wiedemann K, Rietschel M, Laucht M, Wust S, Zimmermann US (2011) An interaction between a neuropeptide Y gene polymorphism and early adversity modulates endocrine stress responses. Psychoneuroendocrinology 36:1010–1020

    Article  CAS  PubMed  Google Scholar 

  • Wittchen HU, Zaudig M, Fydrich T (1997) Structured clinical interview for DSM-IV axis I and II-SCID. Hogrefe, Göttingen

    Google Scholar 

  • Zohsel K, Buchmann AF, Blomeyer D, Hohm E, Schmidt MH, Esser G, Brandeis D, Banaschewski T, Laucht M (2013) Mothers’ prenatal stress and their children’s antisocial outcomes—a moderating role for the dopamine D4 receptor (DRD4) gene. J Child Psychol Psychiatry. doi: 10.1111/jcpp.12138

  • Zucchi FC, Yao Y, Ward ID, Ilnytskyy Y, Olson DM, Benzies K, Kovalchuk I, Kovalchuk O, Metz GA (2013) Maternal stress induces epigenetic signatures of psychiatric and neurological diseases in the offspring. PLoS One 8:e56967

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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This study was supported by grants from the German Research Foundation (DFG) and the Federal Ministry for Education and Research as part of the “Baden-Wuerttemberg Consortium for Addiction Research” and the “National Genome Research Network”.

Conflict of interest and funding

Dr. Banaschewski served in an advisory or consultancy role for Bristol Myers-Sqibb, Desitin, Lilly, Medice, Novartis, Pfizer, Shire, and Viforpharma. He received conference attendance support and conference support or received speaker’s fees from Lilly, Janssen McNeil, Medice, Novartis, and Shire. He is/has been involved in clinical trials conducted by Lilly, Shire, and Novartis. Dr. Zimmermann’s work has been funded by the BMBF, DFG, and NIAAA. Since 2010, he has received compensation for educational talks and workshops from Lundbeck, Gewerkschaft Erziehung und Wissenschaft, Sächsische Landesärztekammer, Park-Krankenhaus Leipzig, Servier, Janssen, GSK, Pfizer, Klinikum Chemnitz. The present work is unrelated to the above grants and relationships. All other authors declare no conflicts of interest.

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Correspondence to Manfred Laucht.

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Arlette F. Buchmann and Katrin Zohsel contributed equally to this work.

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Buchmann, A.F., Zohsel, K., Blomeyer, D. et al. Interaction between prenatal stress and dopamine D4 receptor genotype in predicting aggression and cortisol levels in young adults. Psychopharmacology 231, 3089–3097 (2014). https://doi.org/10.1007/s00213-014-3484-7

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  • DOI: https://doi.org/10.1007/s00213-014-3484-7

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