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

Mihov, Mihail, Shoctor, Hannah, Douglas, Alex, Hay, David C., O'Shaughnessy, Peter J., Iredale, John, Shaw, Sophie, Fowler, Paul and Grassmann, Felix 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 , 105590. 10.1016/j.ebiom.2025.105590

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Elsevier
ISSN:	2352-3964
Date of First Compliant Deposit:	15 May 2025
Date of Acceptance:	22 January 2025
Last Modified:	15 May 2025 10:15
URI:	https://orca.cardiff.ac.uk/id/eprint/178221

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