Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight

This is the author accepted manuscript. The final version is available from the American Medical Association via the DOI in this record.Importance  Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.

Objective  To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.

Design, Setting, and Participants  Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30 487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.

Exposures  Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.

Main Outcome and Measure  Offspring birth weight from 18 studies.

Results  Among the 30 487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10−14) and −4 g (95% CI, −6 to −2g) per SBP-raising allele (P = 1×10−5), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, −394 to −21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.

Conclusions and Relevance  In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.Funding/support of authors is as follows (funding details for individual studies are reported in the Supplement). Drs Frayling and Wood are supported by grant 323195 SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC from the European Research Council; Drs Hattersley and McCarthy are Wellcome Trust senior investigators; Dr McCarthy is a National Institutes of Health Research senior investigator. Dr Freathy is a Sir Henry Dale Fellow (Wellcome Trust and Royal Society grant 104150/Z/14/Z); Dr Tyrrell is funded by a Diabetes Research and Wellness Foundation Fellowship; Dr Richmond is funded by the Wellcome Trust 4-year studentship (grant code, WT083431MF). Drs Lawlor, Davey Smith, Evans, and Ring all work in a unit that receives funding from the University of Bristol and the UK Medical Research Council (grants MC_UU_1201/1/5, MC_UU_1201/1, and MC_UU_1201/4). Dr Lawlor is supported by awards from the Wellcome Trust (WT094529MA and WT088806) and US National Institutes of Health (R01 DK10324) and is a National Institutes of Health Research Senior Investigator (NF-SI-0611-10196). Drs Evans and Medland were supported by an Australian Research Council Future Fellowship (FT130101709 and FT110100548). Dr Järvelin is supported by a DynaHEALTH grant (European Union H2020-PHC-2014; 633595). Dr Feenstra is supported by an Oak Foundation Scholarship. Dr Bouchard is a junior research scholar from the Fonds de la recherché en santé du Québec (FRQS) and a member of the FRQS-funded Centre de recherché du CHUS. Dr M-F. Hivert is a Fonds de la recherché en santé du Québec research scholars and was awarded a Clinical Scientist Award by the Canadian Diabetes Association and the Maud Menten Award from the Institute of Genetics–Canadian Institute of Health Research. Dr Allard was awarded the Canadian Institute of Health Research–Frederick Banting and Charles Best Canada Graduate Scholarships. Dr Jaddoe is supported by the Netherlands Organization for Health Research and Development (ZonMw –VIDI 016.136.361). Dr Morris is a Wellcome Trust Senior Research Fellow (grant number WT098017). Dr Sørensen is holder of a European Research Council Advanced Principal Investigator award