Interaction between oxytocin genotypes and early experience predicts quality of mothering and postpartum mood

Viara Mileva-Seitz, Meir Steiner, Leslie Atkinson, Michael J Meaney, Robert Levitan, James L Kennedy, Marla B Sokolowski, Alison S Fleming, Viara Mileva-Seitz, Meir Steiner, Leslie Atkinson, Michael J Meaney, Robert Levitan, James L Kennedy, Marla B Sokolowski, Alison S Fleming

Abstract

Individual differences in maternal behavior are affected by both early life experiences and oxytocin, but little is known about genetic variation in oxytocin genes and its effects on mothering. We examined two polymorphisms in the oxytocin peptide gene OXT (rs2740210 and rs4813627) and one polymorphism in the oxytocin receptor gene OXTR (rs237885) in 187 Caucasian mothers at six months postpartum. For OXT, both rs2740210 and rs4813627 significantly associated with maternal vocalizing to the infant. These polymorphisms also interacted with the quality of care mothers experienced in early life, to predict variation in maternal instrumental care and postpartum depression. However, postpartum depression did not mediate the gene-environment effects of the OXT SNPs on instrumental care. In contrast, the OXTR SNP rs237885 did not associate with maternal behavior, but it did associate with pre-natal (but not post-natal) depression score. The findings illustrate the importance of variation in oxytocin genes, both alone and in interaction with early environment, as predictors of individual differences in human mothering. Furthermore, depression does not appear to have a causal role on the variation we report in instrumental care. This suggests that variation in instrumental care varies in association with a gene-early environment effect regardless of current depressive symptomatology. Finally, our findings highlight the importance of examining multiple dimensions of human maternal behavior in studies of genetic associations.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Main effects of OXT genotype…
Figure 1. Main effects of OXT genotype on infant-directed vocalizing.
Mothers with C/C and G/G genotypes for rs2740210 and rs4813627, respectively, vocalize significantly longer to their infants; values plotted represent non-imputed values of the original sample; regression coefficients and statistics presented here and in the text are based on multiply imputed values for maternal outcomes (see Methods); ***p

Figure 2. Interaction between OXT genotypes (rs2740210…

Figure 2. Interaction between OXT genotypes (rs2740210 and rs4813627) and maternal self-reported early care quality…

Figure 2. Interaction between OXT genotypes (rs2740210 and rs4813627) and maternal self-reported early care quality (factor derived from multiple early experience measures, see Methods) on (A) duration of instrumental care during a 20 minute maternal-infant recorded interaction and (B) depression score assessed with the CES-D depressioni scale at 6 months postpartum.
Figures do not take into account covariates used in analyses (Tables 3 and 4).

Figure 3. Path models depicting relationships between…

Figure 3. Path models depicting relationships between early experience, postnatal depression, and maternal instrumental care…

Figure 3. Path models depicting relationships between early experience, postnatal depression, and maternal instrumental care in two genotypes of rs2740210: C/C and A/C+A/A using coefficients from Table 6 .
Significance values are based on bias-corrected bootstrap adjusted confidence intervals. Postnatal depression is not a significant mediator of the early care quality associations with instrumental care, for either genotype.
Figure 2. Interaction between OXT genotypes (rs2740210…
Figure 2. Interaction between OXT genotypes (rs2740210 and rs4813627) and maternal self-reported early care quality (factor derived from multiple early experience measures, see Methods) on (A) duration of instrumental care during a 20 minute maternal-infant recorded interaction and (B) depression score assessed with the CES-D depressioni scale at 6 months postpartum.
Figures do not take into account covariates used in analyses (Tables 3 and 4).
Figure 3. Path models depicting relationships between…
Figure 3. Path models depicting relationships between early experience, postnatal depression, and maternal instrumental care in two genotypes of rs2740210: C/C and A/C+A/A using coefficients from Table 6 .
Significance values are based on bias-corrected bootstrap adjusted confidence intervals. Postnatal depression is not a significant mediator of the early care quality associations with instrumental care, for either genotype.

References

    1. Rees SL, Akbari E, Steiner M, Fleming AS (2008) Effects of early deprivation and maternal separation on pup-directed behavior and HPA axis measures in the juvenile female rat. Dev Psychobiol 50: 315–321.
    1. Barrett J, Fleming AS (2011) All mothers are not created equal: neural and psychobiological perspectives on mothering and the importance of individual differences. J Child Psychol Psychiatry 52: 368–397 doi:.
    1. Maestripieri D (2005) Early experience affects the intergenerational transmission of infant abuse in rhesus monkeys. Proc Natl Acad Sci U S A 102: 9726–9729.
    1. Moehler E, Biringen Z, Poustka L (2007) Emotional availability in a sample of mothers with a history of abuse. Am J Orthopsychiatry 77: 624–628 doi:.
    1. Champagne F, Meaney MJ (2001) Like mother, like daughter: evidence for non-genomic transmission of parental behavior and stress responsivity. Prog Brain Res 133: 287–302.
    1. Gonzalez A, Lovic V, Ward GR, Wainwright PE, Fleming AS (2001) Intergenerational effects of complete maternal deprivation and replacement stimulation on maternal behavior and emotionality in female rats. Dev Psychobiol 38: 11–32.
    1. Belsky J, Conger RD, Capaldi DM (2009) The intergenerational transmission of parenting: introduction to the special section. Dev Psychol 45: 1201–1204 doi:.
    1. Egeland B, Bosquet M, Levy A (2002) Continuities and discontinuities in the intergenerational transmission of child maltreatment: Implications for breaking the cycle of abuse. In: K Browne, H Hanks, P. Stratton CH, editor. The prediction and prevention of child abuse: A handbook. New York, NY: John Wiley & Sons. 217–232.
    1. Langeland W, Dijkstra S (1995) Breaking the intergenerational transmission of child abuse: Beyond the mother-child relationship. Child abuse review 4: 4–13 doi:.
    1. Belsky J, Bakermans-Kranenburg MJ, Van IJzendoorn MH (2007) For Better and For Worse: Differential Susceptibility to Environmental Influences. Curr Dir Psychol Sci 16: 300–304 doi:.
    1. Numan M, Fleming AS, Levy F (2006) Maternal behavior. In: Neill JD, editor. Knobil & Neill’s Physiology of Reproduction. New York: Elsevier Inc. 1921–1993.
    1. Insel TR, Shapiro LE (1992) Oxytocin receptors and maternal behavior. Annals Of The New York Academy Of Sciences 652: 122–141.
    1. Febo M, Numan M, Ferris CF (2005) Functional magnetic resonance imaging shows oxytocin activates brain regions associated with mother-pup bonding during suckling. J Neurosci 25: 11637–11644 doi:.
    1. Pedersen CA, Vadlamudi S V, Boccia ML, Amico JA (2006) Maternal behavior deficits in nulliparous oxytocin knockout mice. Genes Brain Behav 5: 274–281 doi:.
    1. Dwyer CM (2008) Individual variation in the expression of maternal behaviour: a review of the neuroendocrine mechanisms in the sheep. J Neuroendocrinol 20: 526–534 doi:.
    1. Keverne EB (1996) Psychopharmacology of maternal behaviour. J Psychopharmacol 10: 16–22 doi:.
    1. Kendrick KM, Keverne EB, Baldwin BA (1986) Intracerebroventricular oxytocin stimulates maternal-behavior in the sheep. Neuroendocrinology 46: 56–61.
    1. Pedersen CA, Caldwell JD, Walker C, Ayers G, Mason GA (1994) Oxytocin activates the postpartum onset of rat maternal behavior in the ventral tegmental and medial preoptic areas. Behav Neurosci 108: 1163.
    1. Francis DD, Champagne F, Meaney MJ (2000) Variations in maternal behaviour are associated with differences in oxytocin receptor levels in the rat. J Neuroendocrinol 12: 1145–1148.
    1. Keverne EB, Kendrick KM, Poindron P (1988) Oxytocin and maternal-behavior. Psychopharmacology (Berl) 96: S30.
    1. Galbally M, Lewis AJ, Ijzendoorn M Van, Permezel M, Van Ijzendoorn MH (2011) The role of oxytocin in mother-infant relations: a systematic review of human studies. Harv Rev Psychiatry 19: 1–14 doi:.
    1. Levine A, Zagoory-Sharon O, Feldman R, Weller A (2007) Oxytocin during pregnancy and early postpartum: individual patterns and maternal-fetal attachment. Peptides 28: 1162–1169 doi:.
    1. Gordon I, Zagoory-Sharon O, Leckman JF, Feldman R (2010) Oxytocin, cortisol, and triadic family interactions. Physiol Behav 101: 679–684 doi:.
    1. Feldman R, Gordon I, Schneiderman I, Weisman O, Zagoory-Sharon O (2010) Natural variations in maternal and paternal care are associated with systematic changes in oxytocin following parent-infant contact. Psychoneuroendocrinology 35: 1133–1141 doi:.
    1. Bakermans-Kranenburg MJ, Van Ijzendoorn MH (2008) Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting. Soc Cogn Affect Neurosci 3: 128–134 doi:.
    1. Feldman R, Zagoory-Sharon O, Weisman O, Schneiderman I, Gordon I, et al. (2012) Sensitive parenting is associated with plasma oxytocin and polymorphisms in the OXTR and CD38 genes. Biol Psychiatry 72: 175–181 doi:.
    1. Champagne F, Diorio J, Sharma S, Meaney MJ (2001) Naturally occurring variations in maternal behavior in the rat are associated with differences in estrogen-inducible central oxytocin receptors. Proc Natl Acad Sci U S A 98: 12736–12741.
    1. Bales KL, Boone E, Epperson P, Hoffman G, Carter CS (2011) Are behavioral effects of early experience mediated by oxytocin? Frontiers in psychiatry 2: 24 doi:.
    1. Winslow JT, Noble PL, Lyons CK, Sterk SM, Insel TR (2003) Rearing effects on cerebrospinal fluid oxytocin concentration and social buffering in rhesus monkeys. Neuropsychopharmacology 28: 910–918 doi:.
    1. Heim C, Young LJ, Newport DJ, Mletzko T, Miller a H, et al. (2009) Lower CSF oxytocin concentrations in women with a history of childhood abuse. Mol Psychiatry 14: 954–958 doi:.
    1. Bakermans-Kranenburg MJ, Van IJzendoorn MH, Riem MME, Tops M, Alink LRA (2011) Oxytocin decreases handgrip force in reaction to infant crying in females without harsh parenting experiences. Soc Cogn Affect Neurosci. doi:.
    1. Field T, Hernandezreif M, Diego M (2006) Intrusive and withdrawn depressed mothers and their infants. Dev Rev 26: 15–30 doi:.
    1. Fleming AS, Ruble DN, Flett GL, Shaul DL (1988) Postpartum adjustment in first-time mothers: Relations between mood, maternal attitudes, and mother-infant interactions. Dev Psychol 24: 71.
    1. Chung EK, McCollum KF, Elo IT, Lee HJ, Culhane JF (2004) Maternal Depressive Symptoms and Infant Health Practices Among Low-Income Women. Pediatrics 113: e523–e529 doi:.
    1. Milgrom J, Westley D, Gemmill A (2004) The mediating role of maternal responsiveness in some longer term effects of postnatal depression on infant development. Infant Behav Dev 27: 443–454 doi:.
    1. Herrera E, Reissland N, Shepherd J (2004) Maternal touch and maternal child-directed speech: effects of depressed mood in the postnatal period. J Affect Disord 81: 29–39 doi:.
    1. Feldman R, Eidelman AI (2007) Maternal postpartum behavior and the emergence of infant–mother and infant–father synchrony in preterm and full-term infants: The role of neonatal vagal tone. Dev Psychobiol 49: 290–302 doi:.
    1. Righetti-Veltema M, Conne-Perréard E, Bousquet A, Manzano J (2002) Postpartum depression and mother-infant relationship at 3 months old. J Affect Disord 70: 291–306.
    1. Saphire-Bernstein S, Way BM, Kim HS, Sherman DK, Taylor SE (2011) Oxytocin receptor gene (OXTR) is related to psychological resources. Proc Natl Acad Sci U S A: 1–5. doi:.
    1. Heim C, Plotsky PM, Nemeroff CB (2004) Importance of studying the contributions of early adverse experience to neurobiological findings in depression. Neuropsychopharmacology 29: 641–648 doi:.
    1. Karevold E, Røysamb E, Ystrom E, Mathiesen KS (2009) Predictors and pathways from infancy to symptoms of anxiety and depression in early adolescence. Dev Psychol 45: 1051–1060 doi:.
    1. Thoits PA (2011) Mechanisms linking social ties and support to physical and mental health. J Health Soc Behav 52: 145–161 doi:.
    1. Skrundz M, Bolten M, Nast I, Hellhammer DH, Meinlschmidt G (2011) Plasma Oxytocin Concentration during Pregnancy is associated with Development of Postpartum Depression. Neuropsychopharmacology: 1–8. doi:.
    1. Thompson RJ, Parker KJ, Hallmayer JF, Waugh CE, Gotlib IH (2011) Oxytocin receptor gene polymorphism (rs2254298) interacts with familial risk for psychopathology to predict symptoms of depression and anxiety in adolescent girls. Psychoneuroendocrinology 36: 144–147 doi:.
    1. Mileva-Seitz V, Kennedy J, Atkinson L, Steiner M, Levitan R, et al. (2011) Serotonin transporter allelic variation in mothers predicts maternal sensitivity, behavior and attitudes toward 6-month-old infants. Genes Brain Behav 10: 325–333 doi:.
    1. Mileva-Seitz V, Fleming AS, Meaney MJ, Mastroianni A, Sinnwell JP, et al. (2012) Dopamine receptors D1 and D2 are related to observed maternal behavior. Genes Brain Behav 11: 684–694 doi:.
    1. Bisceglia R, Jenkins JM, Wigg KG, O’Connor TG, Moran G, et al. (2012) Arginine vasopressin 1a receptor gene and maternal behavior: evidence of association and moderation. Genes Brain Behav 11: 262–268 doi:.
    1. Stivers JA, Kaltwasser MT, Hill PS, Hruby VJ, Crawley JN (1988) Ventral tegmental oxytocin induces grooming. Peptides 9 Suppl 1223–231.
    1. Maestripieri D, Hoffman CL, Anderson GM, Carter CS, Higley JD (2009) Mother-infant interactions in free-ranging rhesus macaques: relationships between physiological and behavioral variables. Physiol Behav 96: 613–619 doi:.
    1. Krpan KM, Coombs R, Zinga D, Steiner M, Fleming AS (2005) Experiential and hormonal correlates of maternal behavior in teen and adult mothers. Horm Behav 47: 112–122 doi:.
    1. Huston AC, Rosenkrantz Aronson S (2005) Mothers’ time with infant and time in employment as predictors of mother–child relationships and children’s early development. Child Dev 76: 467–482.
    1. Kidd KK, Morar B, Castiglione CM, Zhao H, Pakstis a J, et al. (1998) A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus. Hum Genet 103: 211–227.
    1. Tian C, Gregersen PK, Seldin MF (2008) Accounting for ancestry: population substructure and genome-wide association studies. Hum Mol Genet 17: R143–50 doi:.
    1. Ainsworth M, Bell S, Stayton D (1974) Infant-mother attachment and social development: “socialization” as a product of reciprocal responsiveness to signals. In: MPM Richards, editor. The Integration of a Child into a Social World. London: Cambridge University Press. 99–135.
    1. Radloff LS (1977) The CES-D Scale: A Self-Report Depression Scale for Research in the General Population. Appl Psychol Meas 1: 385–401 doi:.
    1. Shafer AB (2006) Meta-analysis of the factor structures of four depression questionnaires: Beck, CES-D, Hamilton, and Zung. J Clin Psychol 62: 123–146 doi:.
    1. Knight RG, Williams S, McGee R, Olaman S (1997) Psychometric properties of the Centre for Epidemiologic Studies Depression Scale (CES-D) in a sample of women in middle life. Behav Res Ther 35: 373–380.
    1. Morin AJS, Moullec G, Maïano C, Layet L, Just J-L, et al. (2011) Psychometric properties of the Center for Epidemiologic Studies Depression Scale (CES-D) in French clinical and nonclinical adults. Revue d’épidémiologie et de santé publique 59: 327–340 doi:.
    1. Caspi A, Moffitt TE, Thornton A, Freedman D, Amwell JW, et al.. (1996) AID-MPR156>;2-E.
    1. Bernstein DP (2003) Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse Negl 27: 169–190 doi:.
    1. Parker G (1990) The parental bonding instrument. Soc Psychiatry Psychiatr Epidemiol 25: 281–282.
    1. Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, et al. (1994) Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry 151: 1132–1136.
    1. Wilhelm K, Niven H, Parker G, Hadzi-Pavlovic D (2005) The stability of the Parental Bonding Instrument over a 20-year period. Psychol Med 35: 387–393.
    1. Gotlib IH, Mount JH, Cordy NI, Whiffen VE (1988) Depression and perceptions of early parenting: a longitudinal investigation. Br J Psychiatry 152: 24–27 doi:.
    1. Strauss JS, Freeman NL, Shaikh S a., Vetró Á, Kiss E, et al.. (2010) No association between oxytocin or prolactin gene variants and childhood-onset mood disorders. Psychoneuroendocrinology: 1422–1428. doi:.
    1. Souza RP, De Luca V, Meltzer HY, Lieberman JA, Kennedy JL (2010) Schizophrenia severity and clozapine treatment outcome association with oxytocinergic genes. Int J Neuropsychopharmacol: 1–6. doi:.
    1. Israel S, Lerer E, Shalev I, Uzefovsky F, Riebold M, et al. (2009) The oxytocin receptor (OXTR) contributes to prosocial fund allocations in the dictator game and the social value orientations task. PLoS One 4: e5535 doi:.
    1. Edwards JR, Lambert LS (2007) Methods for integrating moderation and mediation: a general analytical framework using moderated path analysis. Psychol Methods 12: 1–22 doi:.
    1. Bryant GA, Barrett HC (2007) Recognizing intentions in infant-directed speech: evidence for universals. Psychol Sci 18: 746–751 doi:.
    1. Bornstein MH, Tal J, Rahn C, Galperin CZ, Pêcheux MG, et al. (1992) Functional analysis of the contents of maternal speech to infants of 5 and 13 months in four cultures: Argentina, France, Japan, and the United States. Dev Psychol 28: 593.
    1. Bloom L, Margulis C, Tinker E, Fujita N (1996) Early Conversations and Word Learning: Contributions from Child and Adult. Child Dev 67: 3154–3175 doi:.
    1. Baskerville TA, Douglas AJ (2010) Dopamine and oxytocin interactions underlying behaviors: potential contributions to behavioral disorders. CNS Neurosci Ther 16: e92–123 doi:.
    1. Numan M (2007) Motivational systems and the neural circuitry of maternal behavior in the rat. Dev Psychobiol 49: 12–21 doi:.
    1. Shahrokh DK, Zhang T-Y, Diorio J, Gratton A, Meaney MJ (2010) Oxytocin-dopamine interactions mediate variations in maternal behavior in the rat. Endocrinology 151: 2276–2286 doi:.
    1. Van Ijzendoorn MH, Bakermans-Kranenburg MJ, Mesman J (2008) Dopamine system genes associated with parenting in the context of daily hassles. Genes Brain Behav 7: 403–410 doi:.
    1. Francis DD, Kuhar MJ (2008) Frequency of maternal licking and grooming correlates negatively with vulnerability to cocaine and alcohol use in rats. Pharmacol Biochem Behav 90: 497–500 doi:.
    1. Caldji C, Tannenbaum B, Sharma S, Francis DD, Plotsky PM, et al. (1998) Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc Natl Acad Sci U S A 95: 5335–5340 doi:.
    1. Field T (1992) Infants of depressed mothers. Dev Psychopathol 4: 49–66 doi:.
    1. Costa B, Pini S, Gabelloni P, Abelli M, Lari L, et al. (2009) Oxytocin receptor polymorphisms and adult attachment style in patients with depression. Psychoneuroendocrinology 34: 1506–1514 doi:.
    1. Inoue H, Yamasue H, Tochigi M, Abe O, Liu X, et al. (2010) Association Between the Oxytocin Receptor Gene and Amygdalar Volume in Healthy Adults. Biol Psychiatry 68: 1066–1072 doi:.
    1. Tost H, Kolachana B, Verchinski BA, Bilek E, Goldman AL, et al.. (2011) Neurogenetic effects of OXTR rs2254298 in the extended limbic system of healthy Caucasian adults. Biol Psychiatry 70: e37–9; author reply e41-2. doi:.

Source: PubMed

3
Sottoscrivi