Abstract
Aims/hypothesis: Higher maternal BMI during pregnancy is associated with higher offspring birthweight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed to use genetic variants known to predispose to higher adiposity, coupled with a favourable metabolic profile, in a Mendelian randomisation (MR) study comparing the effect of maternal ‘metabolically favourable adiposity’ on offspring birthweight with the effect of maternal general adiposity (as indexed by BMI). Methods: To test the causal effects of maternal metabolically favourable adiposity or general adiposity on offspring birthweight, we performed two-sample MR. We used variants identified in large, published genetic-association studies as being associated with either higher adiposity and a favourable metabolic profile, or higher BMI (n = 442,278 and n = 322,154 for metabolically favourable adiposity and BMI, respectively). We then extracted data on the metabolically favourable adiposity and BMI variants from a large, published genetic-association study of maternal genotype and offspring birthweight controlling for fetal genetic effects (n = 406,063 with maternal and/or fetal genotype effect estimates). We used several sensitivity analyses to test the reliability of the results. As secondary analyses, we used data from four cohorts (total n = 9323 mother–child pairs) to test the effects of maternal metabolically favourable adiposity or BMI on maternal gestational glucose, anthropometric components of birthweight and cord-blood biomarkers. Results: Higher maternal adiposity with a favourable metabolic profile was associated with lower offspring birthweight (−94 [95% CI −150, −38] g per 1 SD [6.5%] higher maternal metabolically favourable adiposity, p = 0.001). By contrast, higher maternal BMI was associated with higher offspring birthweight (35 [95% CI 16, 53] g per 1 SD [4 kg/m2] higher maternal BMI, p = 0.0002). Sensitivity analyses were broadly consistent with the main results. There was evidence of outlier SNPs for both exposures; their removal slightly strengthened the metabolically favourable adiposity estimate and made no difference to the BMI estimate. Our secondary analyses found evidence to suggest that a higher maternal metabolically favourable adiposity decreases pregnancy fasting glucose levels while a higher maternal BMI increases them. The effects on neonatal anthropometric traits were consistent with the overall effect on birthweight but the smaller sample sizes for these analyses meant that the effects were imprecisely estimated. We also found evidence to suggest that higher maternal metabolically favourable adiposity decreases cord-blood leptin while higher maternal BMI increases it. Conclusions/interpretation: Our results show that higher adiposity in mothers does not necessarily lead to higher offspring birthweight. Higher maternal adiposity can lead to lower offspring birthweight if accompanied by a favourable metabolic profile. Data availability: The data for the genome-wide association studies (GWAS) of BMI are available at https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files. The data for the GWAS of body fat percentage are available at https://walker05.u.hpc.mssm.edu. Graphical abstract: [Figure not available: see fulltext.]
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2790-2802 |
| Number of pages | 13 |
| Journal | Diabetologia |
| Volume | 64 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2021 |
Funding
This study was supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union\u2019s Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement no 669545, the British Heart Foundation (CS/16/4/32482 and AA/18/7/34219) and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. Core funding for ALSPAC is provided by the UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol. 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 data used in this research were funded by 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) and the National Institute for Health Research (NIHR) under its Collaboration for Applied Health Research and Care (CLAHRC) for Yorkshire and Humber and the Clinical Research Network (CRN). The Exeter Family Study of Childhood Health (EFSOCH) was supported by South West NHS Research and Development, Exeter NHS Research and Development, the Darlington Trust and the Peninsula National Institute of Health Research (NIHR) Clinical Research Facility at the University of Exeter. Genotyping of the EFSOCH study samples was funded by Wellcome Trust and Royal Society grant 104150/Z/14/Z. WDT is supported by the GW4 BIOMED DTP awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the UK Medical Research Council (MRC). MCB was supported by a UK MRC Skills Development Fellowship (MR/P014054/1). RMF and RNB were funded by a Wellcome Trust and Royal Society Sir Henry Dale Fellowship (104150/Z/14/Z). MCB, RMF and DAL work in / are affiliated with a unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_00011/6). DAL is an NIHR Senior Investigator (NF-0616-10102). ATH is supported by a NIHR Senior Investigator award and also a Wellcome Trust Senior Investigator award (098395/Z/12/Z). The funders had no role in the design of the study, the collection, analysis or interpretation of the data; the writing of the manuscript, or the decision to submit the manuscript for publication. The views expressed in this paper are those of the authors and not necessarily those of any funder. This research has been conducted using the UKB Resource under application number 7036. We would like to thank the participants and researchers from the UKB who contributed or collected data. We are extremely grateful to all of 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. BiB 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 BiB happen. We are also grateful to the families that took part in EFSOCH and the researchers that collected data. We are grateful to the Genetics of Complex traits team at the University of Exeter (Exeter, UK), for their assistance in learning the methods and navigating the study data; in particular, we are grateful to F. Casanova who helped with the data extraction for BiB and J. Bowden who helped in calculating the F statistic for the BMI genetic instrument. The authors would like to acknowledge the use of the University of Exeter High-Performance Computing (HPC) facility in carrying out this work. DAL has received support from Medtronic Ltd. and Roche Diagnostics for biomarker research that is not related to the study presented in this paper. TMF has received support from GSK, Sanofi and Boehringer Ingelheim that is not related to the study presented in this paper. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.
Keywords
- ALSPAC
- Adiposity
- BMI
- BiB
- EFSOCH
- Glucose
- HAPO
- Insulin
- Mendelian randomisation
- UKB
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
