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Open Access 01-12-2022 | Obesity | Research article

Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomisation using polygenic risk scores

Authors: Tom A. Bond, Rebecca C. Richmond, Ville Karhunen, Gabriel Cuellar-Partida, Maria Carolina Borges, Verena Zuber, Alexessander Couto Alves, Dan Mason, Tiffany C. Yang, Marc J. Gunter, Abbas Dehghan, Ioanna Tzoulaki, Sylvain Sebert, David M. Evans, Alex M. Lewin, Paul F. O’Reilly, Deborah A. Lawlor, Marjo-Riitta Järvelin

Published in: BMC Medicine | Issue 1/2022

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 (P_difference = 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.

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Title: Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomisation using polygenic risk scores
Authors: Tom A. Bond
Rebecca C. Richmond
Ville Karhunen
Gabriel Cuellar-Partida
Maria Carolina Borges
Verena Zuber
Alexessander Couto Alves
Dan Mason
Tiffany C. Yang
Marc J. Gunter
Abbas Dehghan
Ioanna Tzoulaki
Sylvain Sebert
David M. Evans
Alex M. Lewin
Paul F. O’Reilly
Deborah A. Lawlor
Marjo-Riitta Järvelin
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Obesity
Obesity
Published in: BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-021-02216-w

At a glance: The STEP trials

Springer Medicine

Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomisation using polygenic risk scores

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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