Projects per year
Abstract
Background
Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Here, we use Mendelian randomisation (MR) with polygenic risk scores (PRS) to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal.
Methods
We undertook confounder adjusted multivariable (MV) regression and MR using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB, the outcomes were birthweight (BW; N = 9339) and BMI at age 1 and 4 years (N = 8659 to 7575). In ALSPAC only we investigated BMI at 10 and 15 years (N = 4476 to 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10–18 years (N = 2659 to 3855). We compared MR results from several PRS, calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs).
Results
MV and MR consistently showed a positive association between maternal BMI and BW, supporting a moderate causal effect. For adiposity at most older ages, although MV estimates indicated a strong positive association, MR estimates did not support a causal effect. For the PRS with few SNPs, MR estimates were statistically consistent with the null, but had wide confidence intervals so were often also statistically consistent with the MV estimates. In contrast, the largest PRS yielded MR estimates with narrower confidence intervals, providing strong evidence that the true causal effect on adolescent adiposity is smaller than the MV estimates (Pdifference = 0.001 for 15-year BMI). This suggests that the MV estimates are affected by residual confounding, therefore do not provide an accurate indication of the causal effect size.
Conclusions
Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.
Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Here, we use Mendelian randomisation (MR) with polygenic risk scores (PRS) to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal.
Methods
We undertook confounder adjusted multivariable (MV) regression and MR using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB, the outcomes were birthweight (BW; N = 9339) and BMI at age 1 and 4 years (N = 8659 to 7575). In ALSPAC only we investigated BMI at 10 and 15 years (N = 4476 to 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10–18 years (N = 2659 to 3855). We compared MR results from several PRS, calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs).
Results
MV and MR consistently showed a positive association between maternal BMI and BW, supporting a moderate causal effect. For adiposity at most older ages, although MV estimates indicated a strong positive association, MR estimates did not support a causal effect. For the PRS with few SNPs, MR estimates were statistically consistent with the null, but had wide confidence intervals so were often also statistically consistent with the MV estimates. In contrast, the largest PRS yielded MR estimates with narrower confidence intervals, providing strong evidence that the true causal effect on adolescent adiposity is smaller than the MV estimates (Pdifference = 0.001 for 15-year BMI). This suggests that the MV estimates are affected by residual confounding, therefore do not provide an accurate indication of the causal effect size.
Conclusions
Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.
| Original language | English |
|---|---|
| Article number | 34 |
| Number of pages | 16 |
| Journal | BMC Medicine |
| Volume | 20 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Feb 2022 |
Bibliographical note
Funding Information:We thank Tom Palmer, Eleanor Sanderson and Stephen Burgess for helpful discussions; Mark Iles for provision of BiB ethnicity variables; and Amanda Hill and David Hughes for support in delivery and management of the ALSPAC data. We gratefully acknowledge the GIANT (Genetic Investigation of ANthropometric Traits) Consortium for making GWAS summary statistics available. This publication is the work of the authors and may not reflect the views of those acknowledged here. Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization. We are extremely grateful to all the families who took part in ALSPAC, 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. Born in Bradford is only possible because of the enthusiasm and commitment of the Children and Parents in BiB. We are grateful to all the participants, health professionals and researchers who have made Born in Bradford happen. We gratefully acknowledge the contribution of TPP and the TPP ResearchOne team in completing study participant matching to GP primary care records and in providing ongoing informatics support. This research has been conducted using the UK Biobank Resource under applications 10035, 13436 and 236 granting access to the corresponding UK Biobank genetic and phenotype data. We are extremely grateful to all the UK Biobank participants, investigators and team members.
Funding Information:
The UK Medical Research Council and Wellcome (102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Genotyping of the ALSPAC maternal samples was funded by the Wellcome Trust (WT088806) and the offspring samples were genotyped by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). BiB receives core infrastructure funding from the Wellcome Trust (WT101597MA), a joint grant from the UK Medical Research Council (MRC) and UK Economic and Social Science Research Council (ESRC) (MR/N024397/1), the British Heart Foundation (CS/16/4/32482) and the National Institute for Health Research (NIHR) under its Applied Research Collaboration Yorkshire and Humber (NIHR200166). Further support for genome-wide data is from the UK Medical Research Council (G0600705) and the National Institute of Health Research (NF-SI-0611-10196). The work presented here was supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement (669545) and the British Heart Foundation (AA/18/7/34219). TAB is supported by the Medical Research Council (MRC) (UK) (MR/K501281/1); TAB and DME are supported by the NHMRC (Australia) (GNT1183074 and GNT1157714); DAL, TAB, MCB and RCR work in/are affiliated with a unit that is supported by the UK Medical Research Council (MC_UU_00011/1 & MC_UU_00011/6); and DAL is a British Heart Foundation Chair (CH/F/20/90003) and NIHR Senior Investigator (NF-0616-10102). DAL, MCB and TAB are supported by the British Heart Foundation Accelerator Award at the University of Bristol (AA/18/7/34219). MCB’s contribution to this work was supported by a UK MRC Skills Development Fellowship (MR/P014054/1). VK is funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant (721567). MRJ is funded by EU-H2020 LifeCycle Action (733206) which also supports DAL’s research, EU-H2020 EDCMET (825762), EU-H2020 EUCAN Connect (824989), EU H2020-MSCA-ITN-2016 CAPICE Marie Sklodowska-Curie grant (721567) and the MRC (UK) (MRC/BBSRC MR/S03658X/1 [JPI HDHL]). RCR is a de Pass Vice Chancellor’s Research Fellow at the University of Bristol. AL and MRJ are supported by the MRC (UK) (MR/M013138/1) and the European Union Horizon 2020 programme (633595). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Publisher Copyright:
© 2022, The Author(s).
UN SDGs
This output contributes to the following UN Sustainable Development Goals (SDGs)
-
SDG 3 Good Health and Well-being
Research Groups and Themes
- ALSPAC
Keywords
- Obesity
- BMI
- Pregnancy
- Child
- Maternal
- Offspring
- DOHaD
- Mendelian randomisation
Fingerprint
Dive into the research topics of 'Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomisation using polygenic risk scores'. Together they form a unique fingerprint.Projects
- 1 Finished
Equipment
-
HPC (High Performance Computing) and HTC (High Throughput Computing) Facilities
Alam, S. R. (Manager), Williams, D. A. G. (Manager), Eccleston, P. E. (Manager) & Greene, D. (Manager)
Facility/equipment: Facility
Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver