Abstract
There is considerable evidence that smoke exposure during pregnancy (SDP) environmentally influences birth weight after controlling for genetic influences and maternal characteristics. However, maternal smoking during pregnancy—the behavior that leads to smoke exposure during pregnancy—is also genetically-influenced, indicating the potential role of passive gene-environment correlation. An alternative to passive gene-SDP correlation is a cascading effect whereby maternal and child genetic influences are causally linked to prenatal exposures, which then have an ‘environmental’ effect on the development of the child’s biology and behavior. We describe and demonstrate a conceptual framework for disentangling passive rGE from this cascading GE effect using a systems-based polygenic scoring approach comprised of genes shown to be important in the xenobiotic (substances foreign to the body) metabolism pathway. Data were drawn from 5044 families from the Avon Longitudinal Study of Parents and Children with information on maternal SDP, birth weight, and genetic polymorphisms in the xenobiotic pathway. Within a k-fold cross-validation approach (k = 5), we created weighted maternal and child polygenic scores using 18 polymorphisms from 10 genes that have been implicated in the xenobiotic metabolism pathway. Mothers and children shared variation in xenobiotic metabolism genes. Amongst mothers who smoked during pregnancy, neither maternal nor child xenobiotic metabolism polygenic scores were associated with a higher likelihood of smoke exposure during pregnancy, or the severity of smoke exposure during pregnancy (and therefore, neither proposed mechanism was supported), or with child birth weight. SDP was consistently associated with lower child birth weight controlling for the polygenic scores, maternal educational attainment, social class, psychiatric problems, and age. Limitations of the study design and the potential of the framework using other designs are discussed.
Similar content being viewed by others
Notes
Xenobiotic metabolism genes may also be expressed in placental tissue, which represents the second line of defense for the developing child (Blumenfeld et al. Blumenfeld et al. 2009). However, here we focus on maternal and child genetic variation only, as epigenetic information from the placenta is needed to thoroughly investigate this mechanism which is out of the scope of the current manuscript.
We also constructed scores using only the polymorphisms positively associated with conditioning variable in one score and the polymorphisms negatively associated with the conditioning variable in a separate score, and there were no differences in results
References
Agrawal A, Knopik VS, Pergadia ML, Waldron M, Bucholz KK, Martin NG, Madden PA (2008) Correlates of cigarette smoking during pregnancy and its genetic and environmental overlap with nicotine dependence. Nicotine Tob Res 10(4):567–578. doi:10.1080/14622200801978672
Agrawal A, Scherrer JF, Grant JD, Sartor CE, Pergadia ML, Duncan AE, Xian H (2010) The effects of maternal smoking during pregnancy on offspring outcomes. Prev Med 50(1–2):13–18. doi:10.1016/j.ypmed.2009.12.009
Blumenfeld Y, Fan C, Sangkuhl K, Altman R, El-Sayed Y, Quake S (2009) 702: comprehensive maternal-fetal pharmacogenomics—a novel pharmacogenomic thumbprint. Am J Obstet Gynecol 201(6):S254. doi:10.1016/j.ajog.2009.10.719
Boyd A, Golding J, Macleod J, Lawlor DA, Fraser A, Henderson J, Davey Smith G (2013) Cohort profile: the ‘children of the 90 s’—the index offspring of the avon longitudinal study of parents and children. Int J Epidemiol 42(1):111–127. doi:10.1093/ije/dys064
Cicchetti D and Rogosch FA (1996) Equifinality and multifinality in developmental psychopathology. Dev Psychopathol 8(04): 597–600. M593—510.1017/S0954579400007318. Retrieved from href = ”http://dx.doi.org/10.1017/S0954579400007318
Derringer J, Krueger R, Dick D, Aliev F, Grucza R, Saccone S, Bierut L (2012) The aggregate effect of dopamine genes on dependence symptoms among cocaine users: cross-validation of a candidate system scoring approach. Behav Genet 42(4):626–635. doi:10.1007/s10519-012-9531-4
D’Onofrio BM, Turkheimer EN, Eaves LJ, Corey LA, Berg K, Solaas MH, Emery RE (2003) The role of the Children of Twins design in elucidating causal relations between parent characteristics and child outcomes. J Child Psychol Psychiatry 44(8):1130–1144
Dwyer JB, McQuown SC, Leslie FM (2009) The dynamic effects of nicotine on the developing brain. Pharmacol Ther 122(2):125–139. doi:10.1016/j.pharmthera.2009.02.003
Eaves L, Pourcain B, Smith G, York T, Evans D (2014) Resolving the effects of maternal and offspring genotype on dyadic outcomes in genome wide complex trait analysis (“M-GCTA”). Behav Genet 44(5):445–455. doi:10.1007/s10519-014-9666-6
Ernst M, Moolchan ET, Robinson ML (2001) Behavioral and neural consequences of prenatal exposure to nicotine. J Am Acad Child Adolesc Psychiatry 40(6):630–641
Fanaroff AA, Stoll BJ, Wright LL et al (2007) Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 196(2):147e.141–147e.148. doi:10.1016/j.ajog.2006.09.014
Freathy RM, Mook-Kanamori DO, Sovio U, et al (2010). Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nat Genet, 42(5):430–435. http://www.nature.com/ng/journal/v42/n5/suppinfo/ng.567_S1.html
Gaysina D, Fergusson DM, Leve LD, Horwood J, Reiss D, Shaw DS, Harold GT (2013) Maternal smoking during pregnancy and offspring conduct problems: evidence from 3 independent genetically sensitive research designs. JAMA Psychiatry 70(9):956–963. doi:10.1001/jamapsychiatry.2013.127
Hebel JR, Fox NL, Sexton M (1988) Dose-response of birth weight to various measures of maternal smoking during pregnancy. J Clin Epidemiol 41(5):483–489. doi:10.1016/0895-4356(88)90050-9
Herrmann M, King K, Weitzman M (2008) Prenatal tobacco smoke and postnatal secondhand smoke exposure and child neurodevelopment. Curr Opin Pediatr 20(2):184–190. doi:10.1097/MOP.0b013e3282f56165
Horikoshi M, Yaghootkar H, Mook-Kanamori DO, et al (2013) New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism. Nat Genet 45(1):76–82. http://www.nature.com/ng/journal/v45/n1/abs/ng.2477.html#supplementary-information
Hur J, Kim H, Ha EH, Park H, Ha M, Kim Y, Chang N (2013) Birth weight of Korean infants is affected by the interaction of maternal iron intake and GSTM1 polymorphism. J Nutr 143(1):67–73. doi:10.3945/jn.112.161638
Infante-Rivard C, Weinberg CR, Guiguet M (2006) Xenobiotic-metabolizing genes and small-for-gestational-age births: interaction with maternal smoking. Epidemiology 17(1):38–46
Juárez SP, Merlo J (2013) Revisiting the effect of maternal smoking during pregnancy on offspring birthweight: a quasi-experimental sibling analysis in Sweden. PLoS ONE 8(4):e61734. doi:10.1371/journal.pone.0061734
Juhasz G, Hullam G, Eszlari N, Gonda X, Antal P, Anderson IM, Bagdy G (2014) Brain galanin system genes interact with life stresses in depression-related phenotypes. Proc Natl Acad Sci 111(16):E1666–E1673. doi:10.1073/pnas.1403649111
Knopik VS (2009) Maternal smoking during pregnancy and child outcomes: real or spurious effect? Dev Neuropsychol 34(1):462593
Knopik VS, Heath AC, Marceau K, Palmer RH, McGeary JE, Todorov A, Schettini Evans A (2015a) Missouri mothers and their children: a family study of the effects of genetics and the prenatal environment. Twin Res Hum Genet 18(5):485–496
Knopik VS, Marceau K, Palmer RH, Smith TF, Heath AC (2015b) Maternal smoking during pregnancy and offspring birth weight: a genetically-informed approach comparing multiple raters. Behav Genet. doi:10.1007/s10519-015-9750-6
Kramer MS (1987) Determinants of low birth weight: methodological assessment and meta-analysis. Bull World Health Organ 65(5):663–737. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491072/
Kramer MS, Goulet L, Lydon J, Seguin L, McNamara H, Dassa C, Koren G (2001) Socio-economic disparities in preterm birth: causal pathways and mechanisms. Paediatr Perinat Epidemiol 15(suppl 2):104–123
McIntire DD, Bloom SL, Casey BM, Leveno KJ (1999) Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med 340(16):1234–1238. doi:10.1056/NEJM199904223401603
McNeil TF (1995) Perinatal risk factors and schizophrenia: selective review and methodological concerns. Epidemiol Rev 17(1):107–112. http://epirev.oxfordjournals.org/content/17/1/107.short
Milberger S, Biederman J, Faraone SV, Chen L et al (1996) Is maternal smoking during pregnancy a risk factor for attention deficit hyperactivity disorder in children? Am J Psychiatry 153(9):1138–1142
Narusyte J, Neiderhiser JM, D’Onofrio B, Reiss D, Spotts EL, Ganiban J, Lichtenstein P (2008) Testing different types of genotype-environment correlation: an extended chidlren-of-twins model. Dev Psychol 44(6):1591–1603
Nukui T, Day RD, Sims CS, Ness RB, Romkes M (2004) Maternal/newborn GSTT1 null genotype contributes to risk of preterm, low birthweight infants. Pharmacogenetics 14(9):569–576
Pickett KE, Kasza K, Biesecker G, Wright RJ, Wakschlag LS (2009) Women who remember, women who do not: a methodological study of maternal recall of smoking in pregnancy. Nicotine Tob Res 11(10):1166–1174. doi:10.1093/ntr/ntp117
Plomin R (2014) Genotype-environment correlation in the era of DNA. Behav Genet 44(6):629–638. doi:10.1007/s10519-014-9673-7
Purcell SM, Wray NR, Stone JL, et al (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460(7256):748–752. http://www.nature.com/nature/journal/v460/n7256/suppinfo/nature08185_S1.html
Reich W, Todd RD, Joyner CA, Neuman RJ, Heath AC (2003) Reliability and stability of mothers’ reports about their pregnancies with twins. Twin Res Hum Genet 6(02):85–88. doi:10.1375/twin.6.2.85
Rice F, Harold GT, Bolvin J, Hay DF, Van den Bree M, Thapar A (2009) Disentangling prenatal and inherited influences in humans with an experimental design. PNAS 106(7):2464–2467
Salvatore JE, Aliev F, Edwards AC, Evans DM, Macleod J, Hickman M, Dick DM (2014) Polygenic scores predict alcohol problems in an independent sample and show moderation by the environment. Genes 5(2):330–346
Sharma E, Mustafa M, Pathak R, Guleria K, Ahmed RS, Vaid NB, Banerjee BD (2012) A case control study of gene environmental interaction in fetal growth restriction with special reference to organochlorine pesticides. Eur J Obstet Gynecol Reprod Biol 161(2):163–169. doi:10.1016/j.ejogrb.2012.01.008
Stone WL, Bailey B, Khraisha N (2014) The pathophysiology of smoking during pregnancy: a systems biology approach. Front Biosci (Elite Ed) 6:318–328
Thapar A, Fowler T, Rice F, et al (2003) Maternal smoking during pregnancy and attention deficit hyperactivity disorder symptoms in offspring. 1985–1989
Thorgeirsson TE, Gudbjartsson DF, Surakka I, Vink JM, Amin N, Geller F, Laitinen J (2010) Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet 42(5):448–453
Ward C, Lewis S, Coleman T (2007) Prevalence of maternal smoking and environmental tobacco smoke exposure during pregnancy and impact on birth weight: retrospective study using Millennium Cohort. BMC Pub Health 7(1):81. http://www.biomedcentral.com/1471-2458/7/81
Yang J, Lee SH, Goddard ME, Visscher PM (2011) GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88(1):76–82. doi:10.1016/j.ajhg.2010.11.011
Acknowledgments
We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and the Wellcome Trust (Grant Ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. We sincerely thank Lindon Eaves for his thoughtful feedback on the model and conceptual approach. This publication is the work of the authors and K Marceau, R Palmer, JM Neiderhiser, T Smith, & VS Knopik will serve as guarantors for the contents of this paper. Authors were supported by the following sources: T32MH019927 and T32DA016184 (Marceau), K01AA021113 (Palmer), MH092118 (Neiderhiser), T32MH19927 (Smith), DA023134 (Knopik).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. Informed consent was obtained from all individual participants included in the study.
Rights and permissions
About this article
Cite this article
Marceau, K., Palmer, R.H.C., Neiderhiser, J.M. et al. Passive rGE or Developmental Gene-Environment Cascade? An Investigation of the Role of Xenobiotic Metabolism Genes in the Association Between Smoke Exposure During Pregnancy and Child Birth Weight. Behav Genet 46, 365–377 (2016). https://doi.org/10.1007/s10519-016-9778-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10519-016-9778-2