Linking epidemiology and genomics of maternal smoking during pregnancy in utero and in ageing: a population-based study using human foetuses and the UK Biobank cohort

Mihail Mihov; Hannah  Shoctor; Alex Douglas; David C Hay; Peter J. O'Shaughnessy; John P Iredale; Sophie Shaw; Paul Alfred François Fowler; Felix Grassmann

doi:10.1016/j.ebiom.2025.105590

Linking epidemiology and genomics of maternal smoking during pregnancy in utero and in ageing: a population-based study using human foetuses and the UK Biobank cohort

Mihail Mihov^* (Corresponding Author), Hannah Shoctor, Alex Douglas, David C Hay, Peter J. O'Shaughnessy, John P Iredale, Sophie Shaw, Paul Alfred François Fowler , Felix Grassmann

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Maternal smoking and foetal exposure to nicotine and other harmful chemicals in utero remains a serious public health issue with little knowledge about the underlying genetics and consequences of maternal smoking in ageing individuals. Here, we investigated the epidemiology and genomic architecture of maternal smoking in a middle-aged population and compare the results to effects observed in the developing foetus.

METHODS: In the current project, we included 351,562 participants from the UK Biobank (UKB) and estimated exposure to maternal smoking status during pregnancy through self-reporting from the UKB participants about the mother's smoking status around their birth. In addition, we analysed 64 foetal liver transcriptomic expression datasets collected from women seeking elective pregnancy terminations. Foetal maternal smoking exposure was confirmed through measurement of foetal plasma cotinine levels.

FINDINGS: Foetal exposure to maternal smoking had a greater impact on males than females, with more differentially expressed genes in liver tissue (3313 vs. 1163) and higher liver pathway activation. In the UKB, maternal smoking exposure was linked to an unhealthy lifestyle, lower education, and liver damage. In a genome-wide analysis in the UKB, we leveraged the shared genetic basis between affected offspring and their mothers and identified five genome-wide significant regions. We found a low heritability of the trait (∼4%) and implicated several disease-related genes in a transcriptome-wide association study. Maternal smoking increased all-cause mortality risk (Hazard ratio and 95% CI: 1.10 [1.04; 1.16], P = 4.04 × 10 -4), which was attenuated in non-smoking males.

INTERPRETATION: Although male foetuses are more affected than females by maternal smoking in pregnancy, this effect was largely reduced in middle-aged individuals. Importantly, our results highlight that the overall 10% increased mortality due to maternal smoking in pregnancy was greatly attenuated in non-smokers. This study demonstrates the importance of campaigns promoting offspring smoking prevention in families where the parent(s) smoke.

FUNDING: Funding for this project was provided by the University of Aberdeen, the Science Initiative Panel of the Institute of Medical Science, the UK Medical Research Council, the Seventh Framework Programme of the European Union under Grant Agreement 212885 (REEF), NHS Grampian Endowments grants and the European Commission Horizon Europe research grant Agreement 101094099 (INITIALISE).

Original language	English
Article number	1055590
Number of pages	18
Journal	EBioMedicine
Volume	114
Early online date	9 Apr 2025
DOIs	https://doi.org/10.1016/j.ebiom.2025.105590
Publication status	Published - Apr 2025

Bibliographical note

Acknowledgements
The current study was conducted under the UK Biobank project 73446. The authors would like to thank (i) the Fowler team members, NHS Grampian research nurses and staff at the Pregnancy Counselling Service for their essential work in recruiting, collecting, and processing foetuses; (ii) the Centre for Genome Enabled Biology and Medicine, University of Aberdeen, for carrying out the RNA sequencing. The RNA sequencing data analysis was supported by use of the University of Aberdeen Maxwell High Performance Computer Cluster.

Data Availability Statement

Data sharing statement: Access to the phenotypes and genotypes of the UK Biobank participants is governed by an application process at https://www.ukbiobank.ac.uk/. The code for the computation of the derived phenotypes, quality control, and all analyses will be hosted on GitHub at https://github.com/GrassmannLab. The summary statistics of the GWAS will be submitted to the GWAS catalogue https://www.ebi.ac.uk/gwas/.

Funding

Funding for this project was provided by a start-up package to FG by the University of Aberdeen (CF95016-10) as well as the Science Initiative Panel of the Institute of Medical Science. The Foetal Human study was funded by the UK Medical Research Council (MR/L010011/1) to PAF, PJOS, DCH, JPI, and AD, as well as by the Seventh Framework Programme of the European Union under Grant Agreement 212885 (REEF) and by NHS Grampian Endowments grants (08/02, 09/12, 13/56, 15/1/010) to PAF.

Funders	Funder number
Medical Research Council	MR/L010011/1
NHS Grampian	08/02, 09/12, 13/56, 15/1/010
European Commission	212885 , 101094099
University of Aberdeen	CF95016-10

Keywords

Humans
Female
Pregnancy
Smoking/adverse effects
United Kingdom/epidemiology
Male
Maternal Exposure/adverse effects
Prenatal Exposure Delayed Effects/epidemiology
Biological Specimen Banks
Middle Aged
Adult
Genomics/methods
Fetus/metabolism
Aging/genetics
Genome-Wide Association Study
Transcriptome
Cohort Studies
UK Biobank

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

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Mihov_etal_EBM_Linking_Epidemiology_And_VoR
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
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Centre for Genome-Enabled Biology and Medicine
Collie-Duguid, E. S. R. (Manager)
School of Medicine, Medical Sciences & Nutrition
Research Facilities: Facility
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Research Facilities: Facility

Cite this

Mihov, M., Shoctor, H., Douglas, A., Hay, D. C., O'Shaughnessy, P. J., Iredale, J. P., Shaw, S., Fowler , P. A. F., & Grassmann, F. (2025). Linking epidemiology and genomics of maternal smoking during pregnancy in utero and in ageing: a population-based study using human foetuses and the UK Biobank cohort. EBioMedicine, 114, Article 1055590. https://doi.org/10.1016/j.ebiom.2025.105590

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title = "Linking epidemiology and genomics of maternal smoking during pregnancy in utero and in ageing: a population-based study using human foetuses and the UK Biobank cohort",

abstract = "BACKGROUND: Maternal smoking and foetal exposure to nicotine and other harmful chemicals in utero remains a serious public health issue with little knowledge about the underlying genetics and consequences of maternal smoking in ageing individuals. Here, we investigated the epidemiology and genomic architecture of maternal smoking in a middle-aged population and compare the results to effects observed in the developing foetus.METHODS: In the current project, we included 351,562 participants from the UK Biobank (UKB) and estimated exposure to maternal smoking status during pregnancy through self-reporting from the UKB participants about the mother's smoking status around their birth. In addition, we analysed 64 foetal liver transcriptomic expression datasets collected from women seeking elective pregnancy terminations. Foetal maternal smoking exposure was confirmed through measurement of foetal plasma cotinine levels.FINDINGS: Foetal exposure to maternal smoking had a greater impact on males than females, with more differentially expressed genes in liver tissue (3313 vs. 1163) and higher liver pathway activation. In the UKB, maternal smoking exposure was linked to an unhealthy lifestyle, lower education, and liver damage. In a genome-wide analysis in the UKB, we leveraged the shared genetic basis between affected offspring and their mothers and identified five genome-wide significant regions. We found a low heritability of the trait (∼4%) and implicated several disease-related genes in a transcriptome-wide association study. Maternal smoking increased all-cause mortality risk (Hazard ratio and 95% CI: 1.10 [1.04; 1.16], P = 4.04 × 10 -4), which was attenuated in non-smoking males. INTERPRETATION: Although male foetuses are more affected than females by maternal smoking in pregnancy, this effect was largely reduced in middle-aged individuals. Importantly, our results highlight that the overall 10% increased mortality due to maternal smoking in pregnancy was greatly attenuated in non-smokers. This study demonstrates the importance of campaigns promoting offspring smoking prevention in families where the parent(s) smoke.FUNDING: Funding for this project was provided by the University of Aberdeen, the Science Initiative Panel of the Institute of Medical Science, the UK Medical Research Council, the Seventh Framework Programme of the European Union under Grant Agreement 212885 (REEF), NHS Grampian Endowments grants and the European Commission Horizon Europe research grant Agreement 101094099 (INITIALISE).",

keywords = "Humans, Female, Pregnancy, Smoking/adverse effects, United Kingdom/epidemiology, Male, Maternal Exposure/adverse effects, Prenatal Exposure Delayed Effects/epidemiology, Biological Specimen Banks, Middle Aged, Adult, Genomics/methods, Fetus/metabolism, Aging/genetics, Genome-Wide Association Study, Transcriptome, Cohort Studies, UK Biobank",

author = "Mihail Mihov and Hannah Shoctor and Alex Douglas and Hay, {David C} and O'Shaughnessy, {Peter J.} and Iredale, {John P} and Sophie Shaw and Fowler, {Paul Alfred Fran{\c c}ois} and Felix Grassmann",

note = "Acknowledgements The current study was conducted under the UK Biobank project 73446. The authors would like to thank (i) the Fowler team members, NHS Grampian research nurses and staff at the Pregnancy Counselling Service for their essential work in recruiting, collecting, and processing foetuses; (ii) the Centre for Genome Enabled Biology and Medicine, University of Aberdeen, for carrying out the RNA sequencing. The RNA sequencing data analysis was supported by use of the University of Aberdeen Maxwell High Performance Computer Cluster.",

year = "2025",

month = apr,

doi = "10.1016/j.ebiom.2025.105590",

language = "English",

volume = "114",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

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TY - JOUR

T1 - Linking epidemiology and genomics of maternal smoking during pregnancy in utero and in ageing

T2 - a population-based study using human foetuses and the UK Biobank cohort

AU - Mihov, Mihail

AU - Shoctor, Hannah

AU - Douglas, Alex

AU - Hay, David C

AU - O'Shaughnessy, Peter J.

AU - Iredale, John P

AU - Shaw, Sophie

AU - Fowler , Paul Alfred François

AU - Grassmann, Felix

N1 - Acknowledgements The current study was conducted under the UK Biobank project 73446. The authors would like to thank (i) the Fowler team members, NHS Grampian research nurses and staff at the Pregnancy Counselling Service for their essential work in recruiting, collecting, and processing foetuses; (ii) the Centre for Genome Enabled Biology and Medicine, University of Aberdeen, for carrying out the RNA sequencing. The RNA sequencing data analysis was supported by use of the University of Aberdeen Maxwell High Performance Computer Cluster.

PY - 2025/4

Y1 - 2025/4

N2 - BACKGROUND: Maternal smoking and foetal exposure to nicotine and other harmful chemicals in utero remains a serious public health issue with little knowledge about the underlying genetics and consequences of maternal smoking in ageing individuals. Here, we investigated the epidemiology and genomic architecture of maternal smoking in a middle-aged population and compare the results to effects observed in the developing foetus.METHODS: In the current project, we included 351,562 participants from the UK Biobank (UKB) and estimated exposure to maternal smoking status during pregnancy through self-reporting from the UKB participants about the mother's smoking status around their birth. In addition, we analysed 64 foetal liver transcriptomic expression datasets collected from women seeking elective pregnancy terminations. Foetal maternal smoking exposure was confirmed through measurement of foetal plasma cotinine levels.FINDINGS: Foetal exposure to maternal smoking had a greater impact on males than females, with more differentially expressed genes in liver tissue (3313 vs. 1163) and higher liver pathway activation. In the UKB, maternal smoking exposure was linked to an unhealthy lifestyle, lower education, and liver damage. In a genome-wide analysis in the UKB, we leveraged the shared genetic basis between affected offspring and their mothers and identified five genome-wide significant regions. We found a low heritability of the trait (∼4%) and implicated several disease-related genes in a transcriptome-wide association study. Maternal smoking increased all-cause mortality risk (Hazard ratio and 95% CI: 1.10 [1.04; 1.16], P = 4.04 × 10 -4), which was attenuated in non-smoking males. INTERPRETATION: Although male foetuses are more affected than females by maternal smoking in pregnancy, this effect was largely reduced in middle-aged individuals. Importantly, our results highlight that the overall 10% increased mortality due to maternal smoking in pregnancy was greatly attenuated in non-smokers. This study demonstrates the importance of campaigns promoting offspring smoking prevention in families where the parent(s) smoke.FUNDING: Funding for this project was provided by the University of Aberdeen, the Science Initiative Panel of the Institute of Medical Science, the UK Medical Research Council, the Seventh Framework Programme of the European Union under Grant Agreement 212885 (REEF), NHS Grampian Endowments grants and the European Commission Horizon Europe research grant Agreement 101094099 (INITIALISE).

AB - BACKGROUND: Maternal smoking and foetal exposure to nicotine and other harmful chemicals in utero remains a serious public health issue with little knowledge about the underlying genetics and consequences of maternal smoking in ageing individuals. Here, we investigated the epidemiology and genomic architecture of maternal smoking in a middle-aged population and compare the results to effects observed in the developing foetus.METHODS: In the current project, we included 351,562 participants from the UK Biobank (UKB) and estimated exposure to maternal smoking status during pregnancy through self-reporting from the UKB participants about the mother's smoking status around their birth. In addition, we analysed 64 foetal liver transcriptomic expression datasets collected from women seeking elective pregnancy terminations. Foetal maternal smoking exposure was confirmed through measurement of foetal plasma cotinine levels.FINDINGS: Foetal exposure to maternal smoking had a greater impact on males than females, with more differentially expressed genes in liver tissue (3313 vs. 1163) and higher liver pathway activation. In the UKB, maternal smoking exposure was linked to an unhealthy lifestyle, lower education, and liver damage. In a genome-wide analysis in the UKB, we leveraged the shared genetic basis between affected offspring and their mothers and identified five genome-wide significant regions. We found a low heritability of the trait (∼4%) and implicated several disease-related genes in a transcriptome-wide association study. Maternal smoking increased all-cause mortality risk (Hazard ratio and 95% CI: 1.10 [1.04; 1.16], P = 4.04 × 10 -4), which was attenuated in non-smoking males. INTERPRETATION: Although male foetuses are more affected than females by maternal smoking in pregnancy, this effect was largely reduced in middle-aged individuals. Importantly, our results highlight that the overall 10% increased mortality due to maternal smoking in pregnancy was greatly attenuated in non-smokers. This study demonstrates the importance of campaigns promoting offspring smoking prevention in families where the parent(s) smoke.FUNDING: Funding for this project was provided by the University of Aberdeen, the Science Initiative Panel of the Institute of Medical Science, the UK Medical Research Council, the Seventh Framework Programme of the European Union under Grant Agreement 212885 (REEF), NHS Grampian Endowments grants and the European Commission Horizon Europe research grant Agreement 101094099 (INITIALISE).

KW - Humans

KW - Female

KW - Pregnancy

KW - Smoking/adverse effects

KW - United Kingdom/epidemiology

KW - Male

KW - Maternal Exposure/adverse effects

KW - Prenatal Exposure Delayed Effects/epidemiology

KW - Biological Specimen Banks

KW - Middle Aged

KW - Adult

KW - Genomics/methods

KW - Fetus/metabolism

KW - Aging/genetics

KW - Genome-Wide Association Study

KW - Transcriptome

KW - Cohort Studies

KW - UK Biobank

U2 - 10.1016/j.ebiom.2025.105590

DO - 10.1016/j.ebiom.2025.105590

M3 - Article

C2 - 40074595

SN - 2352-3964

VL - 114

JO - EBioMedicine

JF - EBioMedicine

M1 - 1055590

ER -

Linking epidemiology and genomics of maternal smoking during pregnancy in utero and in ageing: a population-based study using human foetuses and the UK Biobank cohort

Abstract

Bibliographical note

Data Availability Statement

Funding

Keywords

UN SDGs

Access to Document

Fingerprint

Equipment

Centre for Genome-Enabled Biology and Medicine

"Maxwell" HPC for Research

Cite this