University of Oulu

Wiklund, P., Karhunen, V., Richmond, R., Parmar, P., Rodriguez, A., De Silva, M., Wielscher, M., Rezwan, F., Richardson, T., Veijola, J., Herzig, K-H., Holloway, J., Relton, C., Sebert, S., Järvelin, M-R., DNA methylation links prenatal smoking exposure to later life health outcomes in offspring (2019), Clinical Epigenetics, vol. 11, article number: 97, DOI: 10.1186/s13148-019-0683-4

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

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Author: Wiklund, Petri1,2,3; Karhunen, Ville2; Richmond, Rebecca C.4;
Organizations: 1Center for Life Course Health Research, University of Oulu, Oulu, Finland
2Department of Epidemiology and Biostatistics, Imperial College London, London, UK
3Department of Health Sciences, University of Jyvaskyla, Jyvaskyla, Finland
4MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
5School of Psychology, University of Lincoln, Lincoln, UK
6Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
7Medical Research Center Oulu, Oulu, Finland
8Oulu University Hospital, Oulu, Finland
9Research Unit of Clinical Neuroscience, University of Oulu, Oulu, Finland
10Institute of Biomedicine and Biocenter of Oulu, Oulu, Finland
11Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland
12Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
13Department for Genomics of Common Diseases, School of Medicine, Imperial College London, London, UK
14MRC-PHE Centre for Environment and Health, Imperial College London, London, W2 1PG, UK
15Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.2 MB)
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Language: English
Published: Springer Nature, 2019
Publish Date: 2019-10-28


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: We identify 69 differentially methylated CpGs in 36 genomic regions (P value < 1 × 10⁻⁷) 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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Series: Clinical epigenetics
ISSN: 1868-7075
ISSN-E: 1868-7083
ISSN-L: 1868-7075
Volume: 11
Article number: 97
DOI: 10.1186/s13148-019-0683-4
Type of Publication: A1 Journal article – refereed
Field of Science: 3142 Public health care science, environmental and occupational health
3141 Health care science
Funding: This project was supported by the Academy of Finland EGEA-project (285547), Biocenter, University of Oulu, Finland (75617), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), ERDF European Regional Development Fund grant no. 539/2010 A31592, the EU H2020--PHC-2014 DynaHEALTH action (grant agreements no. 633595), EU H2020-HCO-2004 iHEALTH Action (grant agreement 643774), EU H2020-PHC-2014 ALEC Action (grant agreement no. 633212), EU H2020-SC1-2016-2017 LifeCycle Action (grant agreement no. 733206), EU H2020-MSCA-ITN-2016 CAPICE Action (grant agreement 721567) and MRC grant no. MR/M013138/1. The Isle of Wight Birth Cohort study has been supported by the National Institutes of Health USA (grant no. R01 HL082925 (PI: Arshad), R01 AI091905 and R01 HL132321 (PI: Karmaus), and R01 AI121226 (MPI: Zhang and Holloway) and Asthma UK (grant no. 364). JWH and FIR are supported by the Ageing Lungs in European Cohorts (ALEC) Study (, which has been funded by the European Union’s Horizon 2020 Research and Innovation programme under grant agreement no. 633212. Data contributions by the ALSPAC study were supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_12013_1 and MC_UU_12013_2). This work was also supported by CRUK (grant number C18281/A19169) and the ESRC (grant number ES/N000498/1). 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. The Accessible Resource for Integrated Epigenomics Studies (ARIES) was funded by the UK Biotechnology and Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1). R.C.R is a de Pass VC Research Fellow at the University of Bristol. T.G.R is a UKRI Innovation Research Fellow (MR/S003886/1). GWAS data used to identify the mQTLs for the ALSPAC offspring was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. Genotyping for the ALSPAC women was supported by the Wellcome Trust (grant reference WT088806). A comprehensive list of grant funding is available on the ALSPAC website (
EU Grant Number: (633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
(643774) iHealth-T2D - Family-based intervention to improve healthy lifestyle and prevent Type 2 Diabetes amongst South Asians with central obesity and prediabetes
(733206) LIFECYCLE - Early-life stressors and LifeCycle health
Academy of Finland Grant Number: 285547
Detailed Information: 285547 (Academy of Finland Funding decision)
Copyright information: © The Author(s). 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.