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

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Title: Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomization using polygenic risk scores
Authors: Bond, T
Richmond, R
Karhunen, V
Cuellar-Partida, G
Borges, MC
Zuber, V
Couto Alves, A
Mason, D
Yang, T
Gunter, M
Dehghan, A
Tzoulaki, I
Sebert, S
Evans, D
Lewin, A
O'Reilly, P
Lawlor, D
Jarvelin, M-R
Item Type: Journal Article
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 Randomization (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.
Issue Date: 1-Feb-2022
Date of Acceptance: 2-Dec-2021
URI: http://hdl.handle.net/10044/1/94173
DOI: 10.1186/s12916-021-02216-w
ISSN: 1741-7015
Publisher: BioMed Central
Journal / Book Title: BMC Medicine
Volume: 20
Copyright Statement: © The Author(s). 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Keywords: Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
Obesity
BMI
Pregnancy
Child
Maternal
Offspring
DOHaD
Mendelian randomisation
BODY-MASS INDEX
GESTATIONAL WEIGHT-GAIN
OBESITY
ASSOCIATION
CHILDHOOD
BIRTH
INSTRUMENTS
CHILDREN
HEALTH
BIAS
BMI
Child
DOHaD
Maternal
Mendelian randomisation
Obesity
Offspring
Pregnancy
11 Medical and Health Sciences
General & Internal Medicine
Publication Status: Published
Online Publication Date: 2022-02-01
Appears in Collections:Faculty of Medicine
School of Public Health



This item is licensed under a Creative Commons License Creative Commons