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Cited by 123Epigenetics and DNA MethylationSmoking Behavior and CessationBirth, Development, and Health

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DNA methylation links prenatal smoking exposure to later life health outcomes in offspring

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Wiklund, Petri, Karhunen, Ville, Richmond, Rebecca C., Parmar, Priyanka, Rodriguez, Alina, De Silva, Maneka, Wielscher, Matthias, Rezwan, Faisal I., Richardson, Tom G., Veijola, Juha, Herzig, Karl-Heinz, Holloway, John W., Relton, Caroline L., Sebert, Sylvain, Järvelin, Marjo-Riitta·2019·Clinical Epigenetics
DOI 10.1186/s13148-019-0683-4PMC PMC6604191

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Abstract

BACKGROUND: Maternal smoking during pregnancy is associated with adverse offspring health outcomes across their life course. We hypothesize that DNA methylation is a potential mediator of this relationship. METHODS: We examined the association of prenatal maternal smoking with offspring blood DNA methylation in 2821 individuals (age 16 to 48 years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess whether methylation markers have causal effects on disease outcomes in the offspring. RESULTS: ) associated with exposure to maternal smoking in adolescents and adults. Mendelian randomization analyses provided evidence for a causal role of four maternal smoking-related CpG sites on an increased risk of inflammatory bowel disease or schizophrenia. Further mediation analyses showed some evidence of cg25189904 in GNG12 gene mediating the effect of exposure to maternal smoking on schizophrenia-related outcomes. CONCLUSIONS: DNA methylation may represent a biological mechanism through which maternal smoking is associated with increased risk of psychiatric morbidity in the exposed offspring.

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Fig. 1 Study design and analytical flow of the study. NFBC Northern Finland Birth Cohort, ALSPAC Avon Longitudinal Study of Parents and Children (m = mothers, c = children), IWBC Isle of Wight Birth Cohort. Dagger symbol denotes CpG sites identified previously in the cord blood of newborns exposed to maternal smoking in utero [11]. Asterisk denotes methylation data for persistence analysis
Fig. 1 Study design and analytical flow of the study. NFBC Northern Finland Birth Cohort, ALSPAC Avon Longitudinal Study of Parents and Children (m = mothers, c = children), IWBC Isle of Wight Birth Cohort. Dagger symbol denotes CpG sites identified previously in the cord blood of newborns exposed to maternal smoking in utero [11]. Asterisk denotes methylation data for persistence analysisCC BY · PubMed Central
Fig. 2 Comparison of meta-analysis effect size estimates and their 95% confidence intervals in all participants (x-axis) and never-smokers (y-axis) for the 36 top CpG sites. All effect size estimates are adjusted for study-specific covariates as necessary and meta-analyzed using inverse-variance weighted fixed-effects model
Fig. 2 Comparison of meta-analysis effect size estimates and their 95% confidence intervals in all participants (x-axis) and never-smokers (y-axis) for the 36 top CpG sites. All effect size estimates are adjusted for study-specific covariates as necessary and meta-analyzed using inverse-variance weighted fixed-effects modelCC BY · PubMed Central
Fig. 3 Visualization of the dose-response effect of the intensity of maternal smoking in pregnancy (x-axis) on offspring blood DNA methylation (y-axis) for top four CpG sites in four gene regions (AHRR, CYP1A1, MYO1G, GFI1). Prediction estimates and their 95% confidence intervals plotted based on generalized additive mixed models, with other covariates (offspring sex, body mass index, smoking status, population stratification, and technical covariates) set at their mean (continuous variables) or mode (categorical variables). The density plots represent the distribution of the cigarettes smoked per day in pregnancy. The plots are truncated at five cigarettes per day in pregnancy (containing 94% of full data)
Fig. 3 Visualization of the dose-response effect of the intensity of maternal smoking in pregnancy (x-axis) on offspring blood DNA methylation (y-axis) for top four CpG sites in four gene regions (AHRR, CYP1A1, MYO1G, GFI1). Prediction estimates and their 95% confidence intervals plotted based on generalized additive mixed models, with other covariates (offspring sex, body mass index, smoking status, population stratification, and technical covariates) set at their mean (continuous variables) or mode (categorical variables). The density plots represent the distribution of the cigarettes smoked per day in pregnancy. The plots are truncated at five cigarettes per day in pregnancy (containing 94% of full data)CC BY · PubMed Central
Fig. 4 Longitudinal analysis of association between exposure to maternal smoking and offspring blood DNA methylation. Effect size estimates (adjusted for study-specific covariates and meta-analyzed using inverse-variance weighted fixed-effects model) and their 95% confidence intervals at age 30–31 years (red) and age 46–48 years (blue) for top CpG sites and P values for the test of equality of the effect size estimates
Fig. 4 Longitudinal analysis of association between exposure to maternal smoking and offspring blood DNA methylation. Effect size estimates (adjusted for study-specific covariates and meta-analyzed using inverse-variance weighted fixed-effects model) and their 95% confidence intervals at age 30–31 years (red) and age 46–48 years (blue) for top CpG sites and P values for the test of equality of the effect size estimatesCC BY · PubMed Central
Fig. 5 Mediation analysis examining the indirect effect of maternal smoking during pregnancy on Bipolar II Scale (a) and Hypomanic personality scale (b) through differential methylation of cg25189904 in GNG12. Data are shown as beta estimate for effect size and 95% confidence intervals
Fig. 5 Mediation analysis examining the indirect effect of maternal smoking during pregnancy on Bipolar II Scale (a) and Hypomanic personality scale (b) through differential methylation of cg25189904 in GNG12. Data are shown as beta estimate for effect size and 95% confidence intervalsCC BY · PubMed Central
Fig. 6 A mediation model for the association between maternal smoking and offspring disease outcomes. βa represents the effect estimate for smoking on DNA methylation (CpG = maternal smoking + covariates); βb represents the effect estimate for CpG on disease (disease = CpG + covariates); βc represents the direct effect (no mediation) estimate for maternal smoking on disease (disease = maternal smoking + covariates; βc′ represents the total effect estimate on disease (disease = maternal smoking + covariates + CpG)
Fig. 6 A mediation model for the association between maternal smoking and offspring disease outcomes. βa represents the effect estimate for smoking on DNA methylation (CpG = maternal smoking + covariates); βb represents the effect estimate for CpG on disease (disease = CpG + covariates); βc represents the direct effect (no mediation) estimate for maternal smoking on disease (disease = maternal smoking + covariates; βc′ represents the total effect estimate on disease (disease = maternal smoking + covariates + CpG)CC BY · PubMed Central

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Metadata

Authors
Wiklund, P., Karhunen, V., Richmond, R. C., Parmar, P., Rodriguez, A., De Silva, M., Wielscher, M., Rezwan, F. I., Richardson, T. G., Veijola, J., Herzig, K.-H., Holloway, J. W., Relton, C. L., Sebert, S., & Järvelin, M.-R.
Affiliations
  • Imperial College London (GB)
  • University of Bristol (GB)
  • University of Oulu (FI)
  • University of Southampton (GB)
  • Oulu University Hospital (FI)
  • Poznan University of Medical Sciences (PL)
Corresponding author
Järvelin, Marjo-Riitta
ORCID
Venue
Clinical Epigenetics
Publisher
Springer Science and Business Media LLC
Published
2019-07-01
Volume
11
Issue
1
Pages
97-97
ISSN
  • 1868-7075 (ISSN-L)
  • 1868-7083
DOI
10.1186/s13148-019-0683-4
PMC
PMC6604191
OpenAlex
W2951038195
Cited by
120
References
53
Citations by year
2026: 3 · 2025: 13 · 2024: 14 · 2023: 25 · 2022: 24 · 2021: 29 · 2020: 10 · 2019: 2
FWCI
5.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Clinical Epigenetics (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Bristol Research (University of Bristol) (publishedVersion, cc-by)
  • Lincoln Repository (University of Lincoln) (acceptedVersion)
  • Jyväskylä University Digital Archive (University of Jyväskylä) (submittedVersion, cc-by)
  • ePrints Soton (University of Southampton) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Explore Bristol Research (submittedVersion, cc-by)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
H2020 European Institute of Innovation and Technology (633595)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Smoking Behavior and Cessation
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
Keywords
smoking during pregnancy, prenatal smoking exposure, DNA methylation, epigenetic mediation, inflammatory bowel disease, schizophrenia, psychiatric morbidity, CpG sites, offspring outcomes, birth cohort studies
MeSH terms
Adolescent, Adult, Female, Humans, Longitudinal Studies, Middle Aged, Pregnancy, Prenatal Exposure Delayed Effects, Prospective Studies, Schizophrenia, Smoking, Cohort Studies, Maternal Exposure, CpG Islands, DNA Methylation, Epigenesis, Genetic, GTP-Binding Protein gamma Subunits, Genome-Wide Association Study, Young Adult, Mendelian Randomization Analysis

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