Proxy gene-by-environment Mendelian randomization study of the association between cigarette smoking during pregnancy and offspring mental health

Hannah M. Sallis; Robyn E. Wootton; George Davey Smith; Marcus R. Munafò

doi:10.1093/ije/dyad022

Proxy gene-by-environment Mendelian randomization study of the association between cigarette smoking during pregnancy and offspring mental health

Hannah M. Sallis, Robyn E. Wootton, George Davey Smith, Marcus R. Munafò

Vice Chancellor's Office

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5 Citations (SciVal)

Abstract

Background: Smoking prevalence is higher among individuals with schizophrenia or depression, and previous work has suggested this relationship is causal. However, this may be due to dynastic effects, for example reflecting maternal smoking during pregnancy rather than a direct effect of smoking. We used a proxy gene-by-environment Mendelian randomization approach to investigate whether there is a causal effect of maternal heaviness of smoking during pregnancy on offspring mental health.

Methods: Analyses were performed in the UK Biobank cohort. Individuals with data on smoking status, maternal smoking during pregnancy, a diagnosis of schizophrenia or depression, and genetic data were included. We used participants' genotype (rs16969968 in the CHRNA5 gene) as a proxy for their mothers' genotype. Analyses were stratified on participants' own smoking status in order to estimate the effect of maternal smoking heaviness during pregnancy independently of offspring smoking.

Results: The effect of maternal smoking on offspring schizophrenia was in opposing directions when stratifying on offspring smoking status. Among offspring of never smokers, each additional risk allele for maternal smoking heaviness appeared to have a protective effect [odds ratio (OR) = 0.77, 95% confidence interval (CI) 0.62 to 0.95, P = 0.015], whereas among ever smokers the effect of maternal smoking was in the reverse direction (OR = 1.23, 95% CI 1.05 to 1.45, P = 0.011, Pinteraction <0.001). There was no clear evidence of an association between maternal smoking heaviness and offspring depression.

Conclusions: These findings do not provide clear evidence of an effect of maternal smoking during pregnancy on offspring schizophrenia or depression, which implies that any causal effect of smoking on schizophrenia or depression is direct.

Original language	English
Pages (from-to)	1350-1359
Number of pages	10
Journal	International Journal of Epidemiology
Volume	52
Issue number	5
Early online date	1 Mar 2023
DOIs	https://doi.org/10.1093/ije/dyad022
Publication status	Published - 1 Oct 2023

Data Availability Statement

The UK Biobank dataset used to conduct the research in this paper is available via application directly to the UK Biobank. Applications are assessed for meeting the required criteria for access, including legal and ethics standards. More information regarding data access can be found at [https://www.ukbiobank.ac.uk/enable-your-research].

Acknowledgements

We are grateful to Dr Hannah Jones and Dr Zoe Reed for their helpful suggestions on the analysis. This research has been conducted using the UK Biobank Resource under Application Number 9142. This work uses data provided by patients and collected by the NHS as part of their care and support. Copyright © 2023, NHS England. Re-used with the permission of the NHS England and UK Biobank. All rights reserved. This research used data assets made available by National Safe Haven as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (research which commenced between 1st October 2020 – 31st March 2021 grant ref MC_PC_20029; 1st April 2021 – 30th September 2022 grant ref MC_PC_20058).

Funding

H.M.S., G.D.S. and M.R.M. are all members of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1, MC_UU_00011/7). H.M.S. is also supported by the European Research Council (grant ref.: 758813 MHINT). R.E.W. is supported by a postdoctoral fellowship from the South-Eastern Norway Regional Health Authority (2020024). This work is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Keywords

depression
Mendelian randomization
schizophrenia
smoking

ASJC Scopus subject areas

Epidemiology

UN SDGs

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

Access to Document

10.1093/ije/dyad022Licence: CC BY

Cite this

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title = "Proxy gene-by-environment Mendelian randomization study of the association between cigarette smoking during pregnancy and offspring mental health",

abstract = "Background: Smoking prevalence is higher among individuals with schizophrenia or depression, and previous work has suggested this relationship is causal. However, this may be due to dynastic effects, for example reflecting maternal smoking during pregnancy rather than a direct effect of smoking. We used a proxy gene-by-environment Mendelian randomization approach to investigate whether there is a causal effect of maternal heaviness of smoking during pregnancy on offspring mental health. Methods: Analyses were performed in the UK Biobank cohort. Individuals with data on smoking status, maternal smoking during pregnancy, a diagnosis of schizophrenia or depression, and genetic data were included. We used participants' genotype (rs16969968 in the CHRNA5 gene) as a proxy for their mothers' genotype. Analyses were stratified on participants' own smoking status in order to estimate the effect of maternal smoking heaviness during pregnancy independently of offspring smoking. Results: The effect of maternal smoking on offspring schizophrenia was in opposing directions when stratifying on offspring smoking status. Among offspring of never smokers, each additional risk allele for maternal smoking heaviness appeared to have a protective effect [odds ratio (OR) = 0.77, 95\% confidence interval (CI) 0.62 to 0.95, P = 0.015], whereas among ever smokers the effect of maternal smoking was in the reverse direction (OR = 1.23, 95\% CI 1.05 to 1.45, P = 0.011, Pinteraction <0.001). There was no clear evidence of an association between maternal smoking heaviness and offspring depression. Conclusions: These findings do not provide clear evidence of an effect of maternal smoking during pregnancy on offspring schizophrenia or depression, which implies that any causal effect of smoking on schizophrenia or depression is direct.",

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N2 - Background: Smoking prevalence is higher among individuals with schizophrenia or depression, and previous work has suggested this relationship is causal. However, this may be due to dynastic effects, for example reflecting maternal smoking during pregnancy rather than a direct effect of smoking. We used a proxy gene-by-environment Mendelian randomization approach to investigate whether there is a causal effect of maternal heaviness of smoking during pregnancy on offspring mental health. Methods: Analyses were performed in the UK Biobank cohort. Individuals with data on smoking status, maternal smoking during pregnancy, a diagnosis of schizophrenia or depression, and genetic data were included. We used participants' genotype (rs16969968 in the CHRNA5 gene) as a proxy for their mothers' genotype. Analyses were stratified on participants' own smoking status in order to estimate the effect of maternal smoking heaviness during pregnancy independently of offspring smoking. Results: The effect of maternal smoking on offspring schizophrenia was in opposing directions when stratifying on offspring smoking status. Among offspring of never smokers, each additional risk allele for maternal smoking heaviness appeared to have a protective effect [odds ratio (OR) = 0.77, 95% confidence interval (CI) 0.62 to 0.95, P = 0.015], whereas among ever smokers the effect of maternal smoking was in the reverse direction (OR = 1.23, 95% CI 1.05 to 1.45, P = 0.011, Pinteraction <0.001). There was no clear evidence of an association between maternal smoking heaviness and offspring depression. Conclusions: These findings do not provide clear evidence of an effect of maternal smoking during pregnancy on offspring schizophrenia or depression, which implies that any causal effect of smoking on schizophrenia or depression is direct.

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Proxy gene-by-environment Mendelian randomization study of the association between cigarette smoking during pregnancy and offspring mental health

Abstract

Data Availability Statement

Acknowledgements

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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