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The Interplay between Maternal Smoking and Genes in Offspring Birth Weight.

ABSTRACT: It is well-established that both the child's genetic endowments as well as maternal smoking during pregnancy impact offspring birth weight. In this paper we move beyond the nature versus nurture debate by investigating the interaction between genetic endowments and this critical prenatal environmental exposure - maternal smoking - in determining birth weight. We draw on longitudinal data from the Avon Longitudinal Study of Parents and Children (ALSPAC) study and replicate our results using data from the UK Biobank. Genetic endowments of the children are proxied with a polygenic score that is constructed based on the results of the most recent genome-wide association study of birth weight. We instrument the maternal decision to smoke during pregnancy with a genetic variant (rs1051730) located in the nicotine receptor gene CHRNA3. This genetic variant is associated with the number of cigarettes consumed daily, and we present evidence that this is plausibly the only channel through which the maternal genetic variant affects the child's birth weight. Additionally, we deal with the misreporting of maternal smoking by using measures of cotinine, a biomarker of nicotine, collected from the mother's urine during their pregnancy. We confirm earlier findings that genetic endowments as well as maternal smoking during pregnancy significantly affects the child's birth weight. However, we do not find evidence of meaningful interactions between genetic endowments and an adverse fetal environment, suggesting that the child's genetic predisposition cannot cushion the damaging effects of maternal smoking.

SUBMITTER: Pereira RD

PROVIDER: S-EPMC7654929 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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The Interplay between Maternal Smoking and Genes in Offspring Birth Weight.

Pereira Rita Dias RD Rietveld Cornelius A CA van Kippersluis Hans H

medRxiv : the preprint server for health sciences 20201103

It is well-established that both the child's genetic endowments as well as maternal smoking during pregnancy impact offspring birth weight. In this paper we move beyond the nature <i>versus</i> nurture debate by investigating the interaction between genetic endowments and this critical prenatal environmental exposure - maternal smoking - in determining birth weight. We draw on longitudinal data from the Avon Longitudinal Study of Parents and Children (ALSPAC) study and replicate our results usin ...[more]

PMID: 33173933

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Project description:Low birth weight and gestational maternal smoking have been linked with reduced lung function in children in many cross sectional studies. However, these associations have not yet been assessed with repeated measurements of lung function. Our aim was to investigate the effects of birth weight, gestational age, and gestational maternal smoking on lung function in children at age 10 and 18 years.In the Isle of Wight birth cohort spirometry was performed at age 10 and 18 years. Information on birth weight and gestational age were obtained from hospital records. Mothers were asked about smoking during pregnancy. We employed linear mixed models to estimate the effect of these risk factors on repeated measurements of lung function. We considered maternal asthma, sex, neonatal intensive care unit admission, height, socio-economic status, personal smoking in participants at age 18, body mass index and environmental tobacco smoke exposure as potential confounders. Finally, we used path analysis to determine links between birth weight, gestational age and gestational maternal smoking on lung function at age 10 and 18 years.Linear mixed models showed that with every 1 kg increase in birth weight, Forced expiratory volume in one second (FEV1) increased by 42.6 ± 17.2 mL and Forced expiratory flow between 25% and 75% (FEF25-75) of Forced vital capacity (FVC) increased by 95.5 ± 41.2 mL at age 18 years after adjusting for potential confounders. Path analysis suggested that birth weight had positive direct effects on FEV1 and FEF25-75 and positive indirect effect on FVC at 10 years which were carried forward to 18 years. Additionally, results also suggested a positive association between gestational age and FEV1, FVC and FEF25-75 at ages 10 and 18 years and an inverse association between gestational smoke exposure and FEV1/FVC ratio and FEF25-75 at age 18 years.Higher birth weight and gestational age were associated with higher FEV1, FVC and FEF25-75 and maternal smoking during pregnancy was associated with reduced FEV1/FVC ratio and FEF25-75. The use of path analysis can improve our understanding of underlying "causal" pathways among different prenatal and childhood factors that affect lung function in both pre-adolescent and adolescent periods.

Project description:Several recent population-based studies have linked exposure to maternal smoking during pregnancy to increased risk of severe mental illness in offspring (eg, bipolar disorder, schizophrenia). It is not yet clear, however, whether this association results from causal teratogenic effects or from confounding influences shared by smoking and severe mental illness.To examine the association between smoking during pregnancy and severe mental illness in offspring, adjusting for measured covariates and unmeasured confounding using family-based designs.This study analyzed population register data through December 31, 2013, for a cohort of 1 680 219 individuals born in Sweden from January 1, 1983, to December 31, 2001. Associations between smoking during pregnancy and severe mental illness in offspring were estimated with adjustment for measured covariates. Cousins and siblings who were discordant on smoking during pregnancy and severe mental illness were then compared, which helped to account for unmeasured genetic and environmental confounding by design.Maternal self-reported smoking during pregnancy, obtained from antenatal visits.Severe mental illness, with clinical diagnosis obtained from inpatient and outpatient visits and defined using International Classification of Diseases codes for bipolar disorder and schizophrenia spectrum disorders.Of the 1 680 219 offspring included in the analysis, 816 775 (48.61%) were female. At the population level, offspring exposed to moderate and high levels of smoking during pregnancy had greater severe mental illness rates than did unexposed offspring (moderate smoking during pregnancy: hazard ratio [HR], 1.25; 95% CI, 1.19-1.30; high smoking during pregnancy: HR, 1.51; 95% CI, 1.44-1.59). These associations decreased in strength with increasing statistical and methodologic controls for familial confounding. In sibling comparisons with within-family covariates, associations were substantially weaker and nonsignificant (moderate smoking during pregnancy: HR, 1.09; 95% CI, 0.94-1.26; high smoking during pregnancy: HR, 1.14; 95% CI, 0.96-1.35). The pattern of associations was consistent across subsets of severe mental illness disorders and was supported by further sensitivity analyses.This population- and family-based study failed to find support for a causal effect of smoking during pregnancy on risk of severe mental illness in offspring. Rather, these results suggest that much of the observed population-level association can be explained by measured and unmeasured factors shared by siblings.

Project description:ImportanceMaternal obesity, pregestational type 1 diabetes, and gestational diabetes have been reported to increase the risks for large birth weight and preterm birth in offspring. However, the associations for insulin-treated diabetes and non-insulin-treated type 2 diabetes, as well as the associations for joint diabetes disorders and maternal body mass index, with these outcomes are less well documented.ObjectiveTo examine associations of maternal diabetes disorders, separately and together with maternal underweight or obesity, with the offspring being large for gestational age and/or preterm at birth.Design, setting, and participantsThis population-based cohort study used nationwide registries to examine all live births (n = 649 043) between January 1, 2004, and December 31, 2014, in Finland. The study and data analysis were conducted from April 1, 2018, to October 10, 2018.ExposuresMaternal prepregnancy body mass index, pregestational diabetes with insulin treatment, pregestational type 2 diabetes without insulin treatment, and gestational diabetes.Main outcomes and measuresOffspring large for gestational age (LGA) at birth and preterm delivery. Logistic regression models were adjusted for offspring birth year; parity; and maternal age, country of birth, and smoking status.ResultsOf the 649 043 births, 4000 (0.62%) were delivered by mothers who had insulin-treated diabetes, 3740 (0.57%) by mothers who had type 2 diabetes, and 98 568 (15.2%) by mothers who had gestational diabetes. The mean (SD) age of mothers was 30.15 (5.37) years, and 588 100 mothers (90.6%) were born in Finland. Statistically significant interactions existed between maternal body mass index and diabetes on offspring LGA and prematurity (insulin-treated diabetes: LGA F = 3489.0 and prematurity F = 1316.4 [P < .001]; type 2 diabetes: LGA F = 147.3 and prematurity F = 21.9 [P < .001]; gestational diabetes: LGA F = 1374.6 and prematurity F = 434.3 [P < .001]). Maternal moderate obesity, compared with normal-weight mothers with no diabetes, was associated with a mildly increased risk of having an offspring LGA (1069 [3.5%] vs 5151 [1.5%]; adjusted odds ratio [aOR], 2.45; 95% CI, 2.29-2.62), and mothers with insulin-treated diabetes had markedly elevated risks of having an offspring LGA (1585 [39.6%] vs 5151 [1.5%]; aOR, 43.80; 95% CI, 40.88-46.93) and a preterm birth (1483 [37.1%] vs 17 481 [5.0%]; aOR, 11.17; 95% CI, 10.46-11.93). Mothers who were moderately obese with type 2 diabetes were at increased risks of LGA (132 [16.4%] vs 5151 [1.5%]; aOR, 12.44; 95% CI, 10.29-15.03) and prematurity (83 [10.3%] vs 17 481 [5.0%]; aOR, 2.14; 95% CI, 1.70-2.69). Mothers who were moderately obese with gestational diabetes had a milder risk of LGA (1195 [6.7%] vs 5151 [1.5%]; aOR, 4.72; 95% CI, 4.42-5.04). Among spontaneous deliveries, the risks were strongest for moderately preterm births, but insulin-treated diabetes was associated with an increased risk also for very and extremely preterm births.Conclusions and relevanceMaternal insulin-treated diabetes appeared to be associated with markedly increased risks for LGA and preterm births, whereas obesity in mothers with type 2 diabetes had mild to moderately increased risks; these findings may have implications for counseling and managing pregnancies.

Project description:BACKGROUND:Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy. One of the most widely reported effects of smoking during pregnancy is reduced birth weight which is in turn associated with chronic disease in adulthood. Epigenome-wide association studies have revealed that smokers show a characteristic "smoking methylation pattern", and recent authors have proposed that DNA methylation mediates the impact of maternal smoking on birth weight. The aims of the present study were to replicate previous reports that methylation mediates the effect of maternal smoking on birth weight, and for the first time to investigate whether the observed mediation effects are sex-specific in order to account for known sex-specific differences in methylation levels. METHODS:Methylation levels in the cord blood of 313 newborns were determined using the Illumina HumanMethylation450K Beadchip. A total of 5,527 CpG sites selected on the basis of evidence from the literature were tested. To determine whether the observed association between maternal smoking and birth weight was attributable to methylation, mediation analyses were performed for significant CpG sites. Separate analyses were then performed in males and females. RESULTS:Following quality control, 282 newborns eventually remained in the analysis. A total of 25 mothers had smoked consistently throughout the pregnancy. The birthweigt of newborns whose mothers had smoked throughout pregnancy was reduced by >200g. After correction for multiple testing, 30 CpGs showed differential methylation in the maternal smoking subgroup including top "smoking methylation pattern" genes AHRR, MYO1G, GFI1, CYP1A1, and CNTNAP2. The effect of maternal smoking on birth weight was partly mediated by the methylation of cg25325512 (PIM1); cg25949550 (CNTNAP2); and cg08699196 (ITGB7). Sex-specific analyses revealed a mediating effect for cg25949550 (CNTNAP2) in male newborns. CONCLUSION:The present data replicate previous findings that methylation can mediate the effect of maternal smoking on birth weight. The analysis of sex-dependent mediation effects suggests that the sex of the newborn may have an influence. Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the sex of the newborn in mediating the association between maternal smoking during pregnancy and birth weight.

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The Interplay between Maternal Smoking and Genes in Offspring Birth Weight.

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The Interplay between Maternal Smoking and Genes in Offspring Birth Weight.

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