Abstract
Background
Congenital heart diseases (CHDs) remain a significant cause of infant morbidity and mortality. Epidemiological studies have explored maternal risk factors for offspring CHDs, but few have used genetic epidemiology methods to improve causal inference.
Methods
Three birth cohorts, including 65,510 mother/offspring pairs (N = 562 CHD cases) were included. We used Mendelian randomisation (MR) analyses to explore the effects of genetically predicted maternal body mass index (BMI), smoking and alcohol on offspring CHDs. We generated genetic risk scores (GRS) using summary data from large-scale genome-wide association studies (GWAS) and validated the strength and relevance of the genetic instrument for exposure levels during pregnancy. Logistic regression was used to estimate the odds ratio (OR) of CHD per 1 standard deviation (SD) higher GRS. Results for the three cohorts were combined using random-effects meta-analyses. We performed several sensitivity analyses including multivariable MR to check the robustness of our findings.
Results
The GRSs associated with the exposures during pregnancy in all three cohorts. The associations of the GRS for maternal BMI with offspring CHD (pooled OR (95% confidence interval) per 1SD higher GRS: 0.95 (0.88, 1.03)), lifetime smoking (pooled OR: 1.01 (0.93, 1.09)) and alcoholic drinks per week (pooled OR: 1.06 (0.98, 1.15)) were close to the null. Sensitivity analyses yielded similar results.
Conclusions
Our results do not provide robust evidence of an effect of maternal BMI, smoking or alcohol on offspring CHDs. However, results were imprecise. Our findings need to be replicated, and highlight the need for more and larger studies with maternal and offspring genotype and offspring CHD data.
Congenital heart diseases (CHDs) remain a significant cause of infant morbidity and mortality. Epidemiological studies have explored maternal risk factors for offspring CHDs, but few have used genetic epidemiology methods to improve causal inference.
Methods
Three birth cohorts, including 65,510 mother/offspring pairs (N = 562 CHD cases) were included. We used Mendelian randomisation (MR) analyses to explore the effects of genetically predicted maternal body mass index (BMI), smoking and alcohol on offspring CHDs. We generated genetic risk scores (GRS) using summary data from large-scale genome-wide association studies (GWAS) and validated the strength and relevance of the genetic instrument for exposure levels during pregnancy. Logistic regression was used to estimate the odds ratio (OR) of CHD per 1 standard deviation (SD) higher GRS. Results for the three cohorts were combined using random-effects meta-analyses. We performed several sensitivity analyses including multivariable MR to check the robustness of our findings.
Results
The GRSs associated with the exposures during pregnancy in all three cohorts. The associations of the GRS for maternal BMI with offspring CHD (pooled OR (95% confidence interval) per 1SD higher GRS: 0.95 (0.88, 1.03)), lifetime smoking (pooled OR: 1.01 (0.93, 1.09)) and alcoholic drinks per week (pooled OR: 1.06 (0.98, 1.15)) were close to the null. Sensitivity analyses yielded similar results.
Conclusions
Our results do not provide robust evidence of an effect of maternal BMI, smoking or alcohol on offspring CHDs. However, results were imprecise. Our findings need to be replicated, and highlight the need for more and larger studies with maternal and offspring genotype and offspring CHD data.
| Original language | English |
|---|---|
| Article number | 35 |
| Number of pages | 12 |
| Journal | BMC Medicine |
| Volume | 21 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Feb 2023 |
Bibliographical note
Funding Information:We are grateful to all the families who took part in the ALSPAC (Avon Longitudinal Study of Parents and Children), the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. BiB (Born in Bradford) study is only possible because of the enthusiasm and commitment of the children and parents. We are grateful to all the participants, practitioners, and researchers who have made the BiB study happen. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this ongoing cohort study. We thank the Norwegian Institute of Public Health (NIPH) for generating high-quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (#223273), Southeast Norway Health Authorities and Stiftelsen Kristian Gerhard Jebsen. We further thank the Center for Diabetes Research, the University of Bergen for providing genotype data and performing quality control and imputation of the data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authorities.
Funding Information:
We are grateful to all the families who took part in the ALSPAC (Avon Longitudinal Study of Parents and Children), the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. BiB (Born in Bradford) study is only possible because of the enthusiasm and commitment of the children and parents. We are grateful to all the participants, practitioners, and researchers who have made the BiB study happen. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this ongoing cohort study. We thank the Norwegian Institute of Public Health (NIPH) for generating high-quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (#223273), Southeast Norway Health Authorities and Stiftelsen Kristian Gerhard Jebsen. We further thank the Center for Diabetes Research, the University of Bergen for providing genotype data and performing quality control and imputation of the data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authorities.
Funding Information:
Core funding for ALSPAC is provided by the UK Medical Research Council and Wellcome (217,065/Z/19/) and the University of Bristol. Many grants have supported different data collections, including for some of the data used in this publication, and a comprehensive list of grant funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant‐acknowledgements.pdf ). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. BiB study has received core support from Wellcome Trust (WT101597MA), a joint grant from the UK Medical Research Council and UK Economic and Social Science Research Council (MR/N024397/1), the British Heart Foundation (CS/16/4/32482), and the NIHR Applied Research Collaboration Yorkshire and Humber (NIHR200166) and Clinical Research Network. The views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research.
Funding Information:
K. Taylor is supported by a British Heart Foundation Doctoral Training Program (FS/17/60/33474). K. Taylor, Dr Wootton, Q. Yang, Dr Borges, and Prof Lawlor work in a unit that is supported by the University of Bristol and the UK Medical Research Council (MC_UU_00011/6). Prof Lawlor is supported by a British Heart Foundation Chair in Cardiovascular Science and Clinical Epidemiology (CH/F/20/90003) and a NIHR Senior Investigator (NF‐0616‐10102). Prof Caputo is supported by the British Heart Foundation Chair in Congenital Heart Disease (CH/1/32804). Dr. Magnus has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 947684). This research was also supported by the Research Council of Norway through its Centres of Excellence funding scheme (Project No. 262700). Dr Wootton is supported by a postdoctoral fellowship from the Norwegian South-Eastern Regional Health Authority (2020024). Q. Yang is funded by a China Scholarship Council PhD Scholarship (CSC201808060273). Dr Borges is supported by the University of Bristol Vice-Chancellor’s Fellowship. Prof Lawlor and Dr Borges are supported by the British Heart Foundation (AA/18/1/34219).
Publisher Copyright:
© 2023, The Author(s).