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Tyrrell J, Richmond RC, Palmer TM, et al. Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight. JAMA. 2016;315(11):1129–1140. doi:10.1001/jama.2016.1975

Genetic evidence for causal relationships between maternal obesity-related traits and birth weight

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Author: Tyrrell, Jessica1,2; Richmond, Rebecca C.3,4,5; Palmer, Tom M.6,7;
Organizations: 1Univ Exeter, Royal Devon & Exeter Hosp, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England.
2Univ Exeter, Knowledge Spa, European Ctr Environm & Human Hlth, Truro, England.
3Univ Bristol, Sch Social & Community Med, Bristol, Avon, England.
4Univ Med Ctr Rotterdam, Erasmus MC, Generat Study Grp R, Rotterdam, Netherlands.
5Univ Bristol, Integrat Epidemiol Unit, Med Res Council, Bristol BS8 1TH, Avon, England.
6Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England.
7Univ Lancaster, Dept Math & Stat, Lancaster, England.
8Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark.
9Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA.
10St Thomas Hosp, Kings Coll London, Dept Twin Res, London, England.
11Wolfson Inst Prevent Med, Ctr Environm & Prevent Med, Barts, England.
12Queen Mary Univ London, London Sch Med & Dent, London, England.
13UCL, UCL Inst Child Hlth, Populat Policy & Practice, London WC1E 6BT, England.
14Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA.
15Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX1 2JD, England.
16Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
17Norwegian Inst Publ Hlth, Dept Genes & Environm, Div Epidemiol, Oslo, Norway.
18Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA.
19Univ Copenhagen, Fac Hlth Sci, COPSAC, Copenhagen, Denmark.
20Copenhagen Univ Hosp, Danish Pediat Asthma Ctr, Gentofte, Denmark.
21Univ Oulu, Inst Hlth Sci, Oulu, Finland.
22Royal Brisbane Hosp, QIMR Berghofer Med Res Inst, Herston, Qld, Australia.
23Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.
24Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands.
25Univ Sherbrooke, Dept Math, Quebec City, PQ, Canada.
26CHU Sherbrooke, Ctr Rech, Quebec City, PQ, Canada.
27Chicoutimi Hosp, ECOGENE & Lipid Clin 21, Quebec City, PQ, Canada.
28Univ Sherbrooke, Dept Biochem, Quebec City, PQ, Canada.
29Imperial Coll London, Dept Primary Care & Publ Hlth, London, England.
30Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia.
31Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA.
32Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA.
33Univ Helsinki, FIMM Inst Mol Med Finland, Helsinki, Finland.
34Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
35Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.
36Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res NIHR, Oxford OX3 7LJ, England.
37Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA.
38Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England.
39Univ Potsdam, Inst Nutr Sci, Potsdam, Germany.
40Charite, Ctr Cardiovasc Res, Berlin, Germany.
41Imperial Coll London, Fac Med, Hlth Protect Agcy Ctr Environm & Hlth, Med Res Council,Sch Publ Hlth,Dept Epidemiol & Bi, London, England.
42Sahlgrens Univ Hosp, Dept Obstet & Gynecol, S-41345 Gothenburg, Sweden.
43Bispebjerg & Frederiksberg Univ Hosp, Inst Prevent Med, Copenhagen, Denmark.
44Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metabol Res, Copenhagen, Denmark.
45Univ Copenhagen, Fac Hlth & Med Sci, Dept Publ Hlth, Copenhagen, Denmark.
46Natl Inst Hlth andWelfare, Dept Children & Young People & Families, Oulu, Finland.
47Univ Oulu, Bioctr Oulu, Oulu, Finland.
48Oulu Univ Hosp, Unit Primary Care, Oulu, Finland.
49Univ So Denmark, Inst Clin Res, Res Unit Obstet & Gynecol, Odense, Denmark.
50Univ Med Ctr Rotterdam, Erasmus MC, Dept Pediat, Rotterdam, Netherlands.
51Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA.
52Jinan Univ, Affiliated Hosp 1, Guangzhou, Guangdong, Peoples R China.
53Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA.
54Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA.
55Univ Sherbrooke, Dept Med, Quebec City, PQ, Canada.
56Univ S Australia, Sch Hlth Sci, Ctr Populat Hlth Res, Adelaide, SA 5001, Australia.
57Univ S Australia, Sansom Inst, Adelaide, SA 5001, Australia.
58South Australian Hlth & Med Res Inst, Adelaide, SA, Australia.
59Univ Bristol, MRC Integrat Epidemiol Unit, Oakfield Rd, Bristol BS8 2BN, Avon, England.
60Royal Devon & Exeter Hosp, Inst Biomed & Clin Sci, Univ Exeter, Barrack Rd, Exeter EX2 5DW, Devon, England.
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 1.9 MB)
Persistent link:
Language: English
Published: American Medical Association, 2016
Publish Date: 2019-05-09


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.

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Series: JAMA. The journal of the American Medical Association
ISSN: 0098-7484
ISSN-E: 1538-3598
ISSN-L: 0098-7484
Volume: 315
Issue: 11
Pages: 1129 - 1140
DOI: 10.1001/jama.2016.1975
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: 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), US National Institutes of Health (R01 DK10324), and European Research Council (669545), 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.
EU Grant Number: (633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
Copyright information: © 2016, American Medical Association.