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

  • Thompson, William D1
  • Beaumont, Robin N1
  • Kuang, Alan2
  • Warrington, Nicole M3, 4, 5
  • Ji, Yingjie1
  • Tyrrell, Jessica1
  • Wood, Andrew R1
  • Scholtens, Denise M2
  • Knight, Bridget A6
  • Evans, David M3, 4
  • Lowe, William L Jr7
  • Santorelli, Gillian8
  • Azad, Raq9
  • Mason, Dan8
  • Hattersley, Andrew T1
  • Frayling, Timothy M1
  • Yaghootkar, Hanieh1
  • Borges, Maria Carolina3, 10
  • Lawlor, Deborah A3, 10, 11
  • Freathy, Rachel M1, 3
  • 1 Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
  • 2 Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 3 MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.
  • 4 University of Queensland Diamantina Institute, University of Queensland, Brisbane QLD 4102, Australia. , (Australia)
  • 5 Department of Public Health and Nursing, NTNU, K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, Postboks 8905, N-7491, Norway. , (Norway)
  • 6 NIHR Exeter Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.
  • 7 Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 8 Bradford Institute for Health Research, Bradford Royal Infirmary, Duckworth Lane, Bradford BD9 6RJ, UK.
  • 9 Department of Biochemistry, Bradford Royal Infirmary, Bradford BD9 6DA, UK.
  • 10 Population Health, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK.
  • 11 Bristol NIHR Biomedical Research Centre, Bristol BS8 2BN, UK.
Published Article
Human Molecular Genetics
Oxford University Press
Publication Date
Jun 04, 2022
DOI: 10.1093/hmg/ddab356
PMID: 34897462


Higher birthweight is associated with higher adult body mass index (BMI). Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether there are fetal effects of recently identified adult metabolically favorable adiposity alleles on birthweight is unknown. We aimed to test the effect on birthweight of fetal genetic predisposition to higher metabolically favorable adult adiposity and compare that with the effect of fetal genetic predisposition to higher adult BMI. We used published genome wide association study data (n = upto 406 063) to estimate fetal effects on birthweight (adjusting for maternal genotype) of alleles known to raise metabolically favorable adult adiposity or BMI. We combined summary data across single nucleotide polymorphisms (SNPs) with random effects meta-analyses. We performed weighted linear regression of SNP-birthweight effects against SNP-adult adiposity effects to test for a dose-dependent association. Fetal genetic predisposition to higher metabolically favorable adult adiposity and higher adult BMI were both associated with higher birthweight (3 g per effect allele (95% CI: 1-5) averaged over 14 SNPs; P = 0.002; 0.5 g per effect allele (95% CI: 0-1) averaged over 76 SNPs; P = 0.042, respectively). SNPs with greater effects on metabolically favorable adiposity tended to have greater effects on birthweight (R2 = 0.2912, P = 0.027). There was no dose-dependent association for BMI (R2 = -0.0019, P = 0.602). Fetal genetic predisposition to both higher adult metabolically favorable adiposity and BMI is associated with birthweight. Fetal effects of metabolically favorable adiposity-raising alleles on birthweight are modestly proportional to their effects on future adiposity, but those of BMI-raising alleles are not. © The Author(s) 2021. Published by Oxford University Press.

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