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Fetal alleles predisposing to metabolically favourable adiposity are associated with higher birth weight

By William David Thompson, Robin Beaumont, Alan Kuang, Nicole Warrington, Y Ji, Jess Tyrrell, A.R. Wood, Denise Scholtens, Bridget A Knight, David M Evans, Bill L Lowe, Gillian Santorelli, Rafaq Azad, Dan Mason, Andrew T Hattersley, Timothy M. Frayling, H. Yaghootkar, Maria Carolina Borges, Deborah A Lawlor, Rachel M Freathy

Posted 19 Sep 2020
bioRxiv DOI: 10.1101/2020.09.17.302208

Background Higher birth weight is associated with higher adult body mass index (BMI). If genetic variants can be identified with alleles that predispose to both greater fetal growth and to greater adult adiposity, such shared genetic effects might indicate biological processes important in the early patterning of adiposity. However, variants identified in genome-wide association studies of adult BMI have overall been only weakly associated with birth weight. Genetic variants have recently been identified where one allele is associated with higher adult body fat percentage, but lower risk of metabolic disease, likely due to a favourable body fat distribution. The effect of these adult metabolically favourable adiposity alleles on an individual’s own birth weight is unknown. Aim We aimed to test the effect on birth weight of a fetal genetic predisposition to higher metabolically favourable adult adiposity and to compare this with the effects of a fetal genetic predisposition to higher adult BMI. We also aimed to examine the effects of a genetic predisposition to higher metabolically favourable adult adiposity or BMI on other birth anthropometric traits (length, ponderal index, head circumference and skinfold thickness) and on cord-blood insulin, leptin and adiponectin. Methods We used published GWAS data from up to 406,063 individuals to estimate the fetal effects on birth weight of alleles that are robustly associated with higher metabolically favourable adult adiposity or BMI. We additionally used 9,350 mother-child pairs from four cohorts to test the effects of the same alleles on other birth anthropometric traits and cord-blood markers. In all analyses, we adjusted for potential confounding due to the maternal genotype. We used inverse-variance weighted meta-analyses to combine summary data across SNPs. Results Fetal genetic predisposition to higher metabolically favourable adult adiposity was associated with higher birth weight (10 grams (95% CI: 7 to 13) higher mean birth weight per 1 SD pooled “genetic score”). Fetal genetic predisposition to higher adult BMI was also associated with higher birth weight, but with a smaller magnitude of effect (4 grams (95% CI: 0 to 8) higher mean birth weight per 1 SD pooled “genetic score”) and with higher heterogeneity across SNPs. Effects on other birth anthropometric outcomes were consistent with the effect on birth weight but with wider confidence intervals. There was no strong evidence for an effect on cord-blood markers. Conclusions Some genetic variants previously linked to adult adiposity influence birth weight. Alleles that predispose to higher metabolically favourable adult adiposity collectively have a stronger effect on birth weight than those predisposing to higher BMI. This suggests that the early accumulation of a metabolically favourable fat distribution might underlie part of the observed association between higher birth weight and higher adult BMI. Larger samples are needed to clarify the effects on other birth anthropometric measures and cord-blood markers. ### Competing Interest Statement Debbie Lawlor has received support from Medtronic LTD and Roche Diagnostics for biomarker research that is not related to the study presented in this paper. Timothy Frayling has received support from GSK, Sanofi, Boehringer Ingelheim that is not related to the study presented in this paper. The other authors report no conflicts. * ALSPAC : (Avon Longitudinal Study of Parents and Children), BiB : (Born in Bradford), EFSOCH : (Exeter Family Study of Childhood Health), EGG : (Early Growth Genetics consortium), HAPO : (Hyperglycaemia and Adverse Pregnancy Outcomes), SEM : (Structural Equation Modelling), WLM : (Weighted Linear Model)

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