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Thompson WD, Beaumont RN, Kuang A, et al. Higher maternal adiposity reduces offspring birthweight if associated with a metabolically favourable profile. Diabetologia. 2021;64(12):2790-2802doi: 10.1007/s00125-021-05570-9.
Thompson, W. D., Beaumont, R. N., Kuang, A., Warrington, N. M., Ji, Y., Tyrrell, J., Wood, A. R., Scholtens, D. M., Knight, B. A., Evans, D. M., Lowe, W. L., Santorelli, G., Azad, R., Mason, D., Hattersley, A. T., Frayling, T. M., Yaghootkar, H., Borges, M. C., Lawlor, D. A., & Freathy, R. M. (2021). Higher maternal adiposity reduces offspring birthweight if associated with a metabolically favourable profile. Diabetologia, 64(12), 2790-2802. https://doi.org/10.1007/s00125-021-05570-9
Thompson, William D, et al. "Higher maternal adiposity reduces offspring birthweight if associated with a metabolically favourable profile." Diabetologia vol. 64,12 (2021): 2790-2802. doi: https://doi.org/10.1007/s00125-021-05570-9
Thompson WD, Beaumont RN, Kuang A, Warrington NM, Ji Y, Tyrrell J, Wood AR, Scholtens DM, Knight BA, Evans DM, Lowe WL, Santorelli G, Azad R, Mason D, Hattersley AT, Frayling TM, Yaghootkar H, Borges MC, Lawlor DA, Freathy RM. Higher maternal adiposity reduces offspring birthweight if associated with a metabolically favourable profile. Diabetologia. 2021 Dec;64(12):2790-2802. doi: 10.1007/s00125-021-05570-9. Epub 2021 Sep 20. PMID: 34542646; PMCID: PMC8563674.
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Diabetologia. 2021 Dec;64(12):2790-2802. doi: 10.1007/s00125-021-05570-9. Epub 2021 Sep 20.

Higher maternal adiposity reduces offspring birthweight if associated with a metabolically favourable profile.

Diabetologia

William D Thompson, Robin N Beaumont, Alan Kuang, Nicole M Warrington, Yingjie Ji, Jessica Tyrrell, Andrew R Wood, Denise M Scholtens, Bridget A Knight, David M Evans, William L Lowe, Gillian Santorelli, Rafaq Azad, Dan Mason, Andrew T Hattersley, Timothy M Frayling, Hanieh Yaghootkar, Maria Carolina Borges, Deborah A Lawlor, Rachel M Freathy

Affiliations

  1. Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK.
  2. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
  3. Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  4. University of Queensland Diamantina Institute, University of Queensland, Brisbane, QLD, Australia.
  5. K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
  6. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  7. Bradford Institute for Health Research, Bradford Royal Infirmary, Bradford, UK.
  8. Department of Biochemistry, Bradford Royal Infirmary, Bradford, UK.
  9. Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
  10. Bristol NIHR Biomedical Research Centre, Bristol, UK.
  11. Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK. [email protected].
  12. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. [email protected].

PMID: 34542646 PMCID: PMC8563674 DOI: 10.1007/s00125-021-05570-9

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/m

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 .

© 2021. The Author(s).

Keywords: ALSPAC; Adiposity; BMI; BiB; EFSOCH; Glucose; HAPO; Insulin; Mendelian randomisation; UKB

References

  1. McDonald SD, Han Z, Mulla S, Beyene J (2010) Overweight and obesity in mothers and risk of preterm birth and low birth weight infants: systematic review and meta-analyses. BMJ 341:c3428. https://doi.org/10.1136/bmj.c3428 - PubMed
  2. Warrington NM, Beaumont RN, Horikoshi M et al (2019) Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. Nat Genet 51(5):804–814. https://doi.org/10.1038/s41588-019-0403-1 - PubMed
  3. Tyrrell J, Richmond RC, Palmer TM et al (2016) Genetic evidence for causal relationships between maternal obesity-related traits and birth weight. JAMA 315(11):1129–1140. https://doi.org/10.1001/jama.2016.1975 - PubMed
  4. Rossi AC, Mullin P, Prefumo F (2013) Prevention, management, and outcomes of macrosomia: a systematic review of literature and meta-analysis. Obstet Gynecol Surv 68(10):702–709. https://doi.org/10.1097/01.ogx.0000435370.74455.a8 - PubMed
  5. Lawlor DA, Relton C, Sattar N, Nelson SM (2012) Maternal adiposity--a determinant of perinatal and offspring outcomes? Nat Rev Endocrinol 8(11):679–688. https://doi.org/10.1038/nrendo.2012.176 - PubMed
  6. The HAPO Study Cooperative Research Group (2009) Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: associations with neonatal anthropometrics. Diabetes 58(2):453–459. https://doi.org/10.2337/db08-1112 - PubMed
  7. Yaghootkar H, Scott RA, White CC et al (2014) Genetic evidence for a normal-weight “metabolically obese” phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes. Diabetes 63(12):4369. https://doi.org/10.2337/db14-0318 - PubMed
  8. Yaghootkar H, Lotta LA, Tyrrell J et al (2016) Genetic evidence for a link between favorable adiposity and lower risk of type 2 diabetes, hypertension, and heart disease. Diabetes 65(8):2448. https://doi.org/10.2337/db15-1671 - PubMed
  9. Ji Y, Yiorkas AM, Frau F et al (2019) Genome-wide and abdominal MRI data provide evidence that a genetically determined favorable adiposity phenotype is characterized by lower ectopic liver fat and lower risk of type 2 diabetes, heart disease, and hypertension. Diabetes 68(1):207. https://doi.org/10.2337/db18-0708 - PubMed
  10. Lu Y, Day FR, Gustafsson S et al (2016) New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk. Nat Commun 7:10495. https://doi.org/10.1038/ncomms10495 - PubMed
  11. Locke AE, Kahali B, Berndt SI et al (2015) Genetic studies of body mass index yield new insights for obesity biology. Nature 518:197. https://doi.org/10.1038/nature14177 - PubMed
  12. Pulit SL, Stoneman C, Morris AP et al (2018) Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry. Hum Mol Genet 28(1):166–174. https://doi.org/10.1093/hmg/ddy327 - PubMed
  13. Burgess S, Davies NM, Thompson SG (2016) Bias due to participant overlap in two-sample Mendelian randomization. Genet Epidemiol 40(7):597–608. https://doi.org/10.1002/gepi.21998 - PubMed
  14. Horikoshi M, Yaghootkar H, Mook-Kanamori DO et al (2013) New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism. Nat Genet 45(1):76–82. https://doi.org/10.1038/ng.2477 - PubMed
  15. Boyd A, Golding J, Macleod J et al (2013) Cohort profile: the ‘children of the 90s’—the index offspring of the Avon longitudinal study of parents and children. Int J Epidemiol 42(1):111–127. https://doi.org/10.1093/ije/dys064 - PubMed
  16. Fraser A, Macdonald-Wallis C, Tilling K et al (2013) Cohort profile: the Avon longitudinal study of parents and children: ALSPAC mothers cohort. Int J Epidemiol 42(1):97–110. https://doi.org/10.1093/ije/dys066 - PubMed
  17. Wright J, Small N, Raynor P et al (2012) Cohort profile: the Born in Bradford multi-ethnic family cohort study. Int J Epidemiol 42(4):978–991. https://doi.org/10.1093/ije/dys112 - PubMed
  18. Knight B, Shields BM, Hattersley AT (2006) The Exeter Family Study of Childhood Health (EFSOCH): study protocol and methodology. Paediatr Perinat Epidemiol 20(2):172–179. https://doi.org/10.1111/j.1365-3016.2006.00701.x - PubMed
  19. The HAPO Study Cooperative Research (2008) Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 358(19):1991–2002. https://doi.org/10.1056/NEJMoa0707943 - PubMed
  20. Dupuis J, Langenberg C, Prokopenko I et al (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42(2):105–116. https://doi.org/10.1038/ng.520 - PubMed
  21. Warrington NM, Freathy RM, Neale MC, Evans DM (2018) Using structural equation modelling to jointly estimate maternal and fetal effects on birthweight in the UK Biobank. Int J Epidemiol 47(4):1229–1241. https://doi.org/10.1093/ije/dyy015 - PubMed
  22. Stephen B, Dylan SS, Simon GT (2015) A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res 26(5):2333–2355. https://doi.org/10.1177/0962280215597579 - PubMed
  23. Steichen T (2001) METANINF: Stata module to evaluate influence of a single study in meta-analysis estimation. Boston College Department of Economics, Boston, MA - PubMed
  24. Bowden J, Davey Smith G, Burgess S (2015) Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol 44(2):512–525. https://doi.org/10.1093/ije/dyv080 - PubMed
  25. Bowden J, Davey Smith G, Haycock PC, Burgess S (2016) Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol 40(4):304–314. https://doi.org/10.1002/gepi.21965 - PubMed
  26. Davey Smith G, Spiller W, Bowden J et al (2018) Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the radial plot and radial regression. Int J Epidemiol 47(4):1264–1278. https://doi.org/10.1093/ije/dyy101 - PubMed
  27. Sanderson E, Davey Smith G, Windmeijer F, Bowden J (2018) An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings. Int J Epidemiol 48(3):713–727. https://doi.org/10.1093/ije/dyy262 - PubMed
  28. Hwang L-D, Lawlor DA, Freathy RM, Evans DM, Warrington NM (2019) Using a two-sample Mendelian randomization design to investigate a possible causal effect of maternal lipid concentrations on offspring birth weight. Int J Epidemiol 48(5):1457–1467. https://doi.org/10.1093/ije/dyz160 - PubMed
  29. Hay WW Jr (2006) Placental-fetal glucose exchange and fetal glucose metabolism. Trans Am Clin Climatol Assoc 117:321–340 - PubMed
  30. Pigeyre M, Sjaarda J, Mao S et al (2019) Identification of novel causal blood biomarkers linking metabolically favorable adiposity with type 2 diabetes risk. Diabetes Care 42(9):1800. https://doi.org/10.2337/dc18-2444 - PubMed
  31. Winkler TW, Günther F, Höllerer S et al (2018) A joint view on genetic variants for adiposity differentiates subtypes with distinct metabolic implications. Nat Commun 9(1):1946–1946. https://doi.org/10.1038/s41467-018-04124-9 - PubMed
  32. Huang LO, Rauch A, Mazzaferro E et al (2021) Genome-wide discovery of genetic loci that uncouple excess adiposity from its comorbidities. Nat Metab 3(2):228–243. https://doi.org/10.1038/s42255-021-00346-2 - PubMed
  33. Beaumont RN, Warrington NM, Cavadino A et al (2018) Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics. Hum Mol Genet 27(4):742–756. https://doi.org/10.1093/hmg/ddx429 - PubMed
  34. Hartwig FP, Davies NM, Hemani G, Davey Smith G (2016) Two-sample Mendelian randomization: avoiding the downsides of a powerful, widely applicable but potentially fallible technique. Int J Epidemiol 45(6):1717–1726. https://doi.org/10.1093/ije/dyx028 - PubMed

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