NOTE:

The current proposal is for three scientific papers investigating (1) a potential genetic moderation of prenatal environmental conditions on maternal self-reported prenatal stress, (2) a potential genetic moderation of prenatal maternal stress on infant temperament, and (3) a potential interaction between the effects of prenatal and postnatal environmental conditions on socioemotional and behavioural outcomes in childhood.

BACKGROUND: Effects of prenatal stress have been found to predict various negative psychological outcomes across childhood (Glover, 2011). This observation has been interpreted in terms of the fetal programming hypothesis which stipulates that the fetus adjusts its phenotype in utero as a means of adapting to anticipated conditions of the postnatal environment (Barker, 1998). We recently raised the notion that in some cases prenatal stress seems to promote developmental plasticity in the postnatal period rather than foster psychopathology (Pluess & Belsky, 2011). This is based on the observation that infant difficult temperament and cortisol reactivity--both consistently associated with the presence of prenatal stress--moderate the effects of the early care environment for better and for worse. More precisely, children with these characteristics will be more negatively affected by early adversity but also benefit more from a supportive environment, consistent with the differential susceptibility hypothesis which claims that individuals fundamentally differ in their susceptibility to both negative and positive environmental influences as a function of behavioural, physiological or genetic factors (Belsky & Pluess, 2009). Recently, we were able to show that a genetic susceptibility factor--the serotonin transporter polymorphism--moderates the effects of prenatal maternal stress on infant temperament (Pluess et al., in press) using data from the Generation R study, a large Dutch birth cohort study (Jaddoe et al., 2008).

The current proposal aims at further testing the theorised complex relationships between genetic susceptibility of both the mother and fetus to prenatal environmental conditions in the prediction of behavioural susceptibility factors and the consequent moderation of postnatal environmental influences by prenatally programmed susceptibility.

PAPER 1

The first paper we propose seeks to test a gene-environment interaction (GXE) between prenatal environmental conditions and maternal susceptibility genes in the prediction of maternal subjective stress during pregnancy.

RATIONALE: Most studies on the effects of prenatal maternal stress on child development are based on subjective measures of maternal anxiety, depression and perceived stress (Pluess, Bolten, Pirke, & Hellhammer, 2010). The differential susceptibility hypothesis proposes that mothers differ in their susceptibility to environmental effects as a function of genetic differences amongst others. In a recent study mothers carrying susceptibility alleles (COMT val/val, DRD4 7-repeat) were more affected by daily hassles regarding their parenting sensitivity than mothers with different alleles (van IJzendoorn, Bakermans-Kranenburg, & Mesman, 2008). This is consistent with Caspi et al.'s (2003) ground breaking findings that effects of stressful life events on depression are moderated by the serotonin transporter polymorphism. In other words, some individuals will be more affected by environmental conditions than others as a function of genetic differences (Belsky & Pluess, 2009). We want to investigate whether such a GXE also characterises maternal response during pregnancy (i.e. subjective measures of prenatal stress) to objective prenatal stressors.

PRINCIPAL AIMS: We want to overcome limitations of previous studies which ignore individual differences in mothers' susceptibility to prenatal environmental conditions in order to better understand the relationship between objective and subjective measures of prenatal maternal stress as they relate to child outcomes.

PAPER 2

The second paper seeks to replicate and extend recent findings within the Generation R study of a GXE between prenatal stress and genetic susceptibility of the child in the prediciton of infant difficult temperament (Pluess et al., in press).

RATIONAL:Using data from the Generation R study we recently reported that the effects of prenatal stress on infant temperament vary across fetuses due to their genetic make-up (Pluess et al., in press).Infants carrying the short allele of the serotonin transporter polymorphism (5-HTTLPR) were rated as more negatively emotional when mothers reported anxiety during pregnancy while there was no difference between genotypes on negative emotionality when maternal anxiety was low. The association between maternal anxiety during pregnancy and negative emotionality in early infancy was significant in infants carrying one or more copies of the short allele, but not in those homozygous for the long allele. We want to replicate this finding within the ALSPAC data.

Recently, the approach to combine several genes into a cumulative genetic score when investigating GXE has yielded promising results. Belsky and Beaver (in press) found that the more susceptibility genes (of 5 different polymorphisms) adolescents carried the more affected they were regarding their self-regulation by the parenting quality they experienced.We want to investigate whether the effects of prenatal environmental influences on infant temperament are moderated by a composite genetic score based on 4 different genetic polymorphisms (5-HTTLPR, COMT, MAOA, BDNF).

PRINCIPAL AIMS: The proposed paper aims at replicating and extending, within ALSPAC, the GXE that recently emerged in the Generation R data. We want to investigate whether the effects of prenatal environmental influences on infant early temperament are moderated by (1) the 5-HTTLPR, and (2) a composite genetic score based on 4 different genetic polymorphisms (5-HTTLPR, COMT, MAOA, BDNF).

PAPER 3

In the third paper we want to investigate whether postnatal environmental conditions moderate effects of prenatal environmental conditions on socioemotional and behavioural outcomes across childhood.

RATIONAL: Recent empirical evidence suggests that the effects of prenatal stress on child development are dependent on the quality of the postnatal environment. For example, the association between prenatal stress and observed child fearfulness at 17 months postpartum proved to be moderated by attachment security (Bergman, Sarkar, Glover, & O'Connor, 2008). The effect of prenatal stress on child fearfulness was strongest in children with an insecure/resistant attachment. In another study maternal anxiety during pregnancy moderated effects of maternal sensitivity on child mental development with children whose mothers were suffering from anxiety during pregnancy being more susceptible to maternal sensitivity (Grant, McMahon, Reilly, & Austin, 2010). Intriguingly, children of prenatally anxious mothers had the best outcomes when sensitivity was high and the worst when sensitivity was low suggesting that prenatal maternal anxiety increases postnatal susceptibility consistent with the differential susceptibility hypothesis outlined above.

PRINCIPAL AIMS: We want to test, within ALSPAC, whether prenatal stress moderates the effects of postnatal environmental conditions on behaviour problems and social skills across childhood.

CONCLUDING REMARKS: We seek to break new ground in the study of GXE and prenatal programming using the ALSPAC data. Not only will we evaluate whether differential susceptibility characterises the manner in which select polymorphisms moderate environmental influences during the prenatal period on later development, but whether this proves so when one employs cumulative measures of (a) environmental risk/support and (b) genetic plasticity. Indeed, we predict that the more putative plasticity alleles an individual carries, the more cumulative contextual risk/support will predict infant temperament-and in a differential-susceptibility manner. Thus, more genetically malleable or plastic individuals will benefit more than others from environmental support but, at the same time, be more adversely affected by negative environmental conditions.

REFERENCES

Barker, D. J. (1998). In utero programming of chronic disease. Clinical Science, 95(2), 115-128.

Belsky, J., & Beaver, K. M. (in press). Cumulative-genetic plasticity, parenting and adolescent self-control/regulation. Journal of Child Psychology and Psychiatry.

Belsky, J., & Pluess, M. (2009). Beyond Diathesis-Stress: Differential Susceptibility to Environmental Influences. Psychological Bulletin, 135(6), 885-908.

Bergman, K., Sarkar, P., Glover, V., & O'Connor, T. G. (2008). Quality of child-parent attachment moderates the impact of antenatal stress on child fearfulness. Journal of Child Psychology and Psychiatry and Allied Disciplines, 49(10), 1089-1098.

Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., et al. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science, 301(5631), 386-389.

Glover, V. (2011). Annual Research Review: Prenatal stress and the origins of psychopathology: an evolutionary perspective. Journal of Child Psychology and Psychiatry and Allied Disciplines.

Grant, K. A., McMahon, C., Reilly, N., & Austin, M. P. (2010). Maternal sensitivity moderates the impact of prenatal anxiety disorder on infant mental development. Early Human Development, 86(9), 551-556.

Jaddoe, V. W., van Duijn, C. M., van der Heijden, A. J., Mackenbach, J. P., Moll, H. A., Steegers, E. A., et al. (2008). The Generation R Study: design and cohort update until the age of 4 years. European Journal of Epidemiology, 23(12), 801-811.

Pluess, M., & Belsky, J. (2011). Prenatal Programming of Postnatal Plasticity? Development and Psychopathology, 23(1), 29-38.

Pluess, M., Bolten, M., Pirke, K. M., & Hellhammer, D. (2010). Maternal trait anxiety, emotional distress, and salivary cortisol in pregnancy. Biological Psychology, 83(3), 169-175.

Pluess, M., Velders, F. P., Belsky, J., van IJzendoorn, M. H., Bakermans-Kranenburg, M. J., Jaddoe, V. W., et al. (in press). Serotonin Transporter Polymorphism Moderates Effects of Prenatal Maternal Anxiety on Infant Negative Emotionality. Biological Psychiatry.van IJzendoorn, M. H., Bakermans-Kranenburg, M. J., & Mesman, J. (2008). Dopamine system genes associated with parenting in the context of daily hassles. Genes, Brain, and Behavior, 7(4), 403-410.