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

The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.

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

Open access
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

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s13148-019-0683-4

Cites

53 of 53 references verified0 citation errors · 0 not checkable

Statistics

Figures

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

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 53 references

Cited by

Sorted by citations

Related

See all

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review