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Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight
Open accessAbstract
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 -2 g) 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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“We found positive associations of maternal gestational fasting glucose with offspring birthweight in multivariable regression analyses pooled from European origin cohort studies with minimal adjustment for potential confounders.55”
From Triangulation in aetiological epidemiology (2017) · cites this paper as [55]
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“Positive fasting glucose-birthweight effects were also seen in the IV of glucose as an intermediate in an RCT57 and IV MR studies.55”
From Triangulation in aetiological epidemiology (2017) · cites this paper as [55]
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Metadata
- Authors
- Tyrrell, J., Richmond, R. C., Palmer, T. M., Feenstra, B., Rangarajan, J., Metrustry, S., Cavadino, A., Paternoster, L., Armstrong, L. L., De Silva, N. M. G., Wood, A. R., Horikoshi, M., Geller, F., Myhre, R., Bradfield, J. P., Kreiner-Møller, E., Huikari, V., Painter, J. N., Hottenga, J.-J., Allard, C., Berry, D. J., Bouchard, L., Das, S., Evans, D. M., Hakonarson, H., Hayes, M. G., Heikkinen, J., Hofman, A., Knight, B., Lind, P. A., McCarthy, M. I., McMahon, G., Medland, S. E., Melbye, M., Morris, A. P., Nodzenski, M., Reichetzeder, C., Ring, S. M., Sebert, S., Sengpiel, V., Sørensen, T. I. A., Willemsen, G., de Geus, E. J. C., Martin, N. G., Spector, T. D., Power, C., Järvelin, M.-R., Bisgaard, H., Grant, S. F. A., Nohr, E. A., Jaddoe, V. W., Jacobsson, B., Murray, J. C., Hocher, B., Hattersley, A. T., Scholtens, D. M., Davey Smith, G., Hivert, M.-F., Felix, J. F., Hyppönen, E., Lowe, W. L., Frayling, T. M., Lawlor, D. A., Freathy, R. M., & for the Early Growth Genetics (EGG) Consortium
- Affiliations
- University of Exeter (GB)
- Erasmus MC (NL)
- University of Warwick (GB)
- Statens Serum Institut (DK)
- Northwestern University (US)
- St Thomas' Hospital (GB)
- Queen Mary University of London (GB)
- University of Bristol (GB)
- Medical Research Council Integrative Epidemiology Unit at the University of Bristol, United Kingdom
- Centre for Human Genetics (GB)
- Norwegian Institute of Public Health (NO)
- Children's Hospital of Philadelphia (US)
- Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark, and Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark
- University of Oulu (FI)
- QIMR Berghofer Medical Research Institute (AU)
- Amsterdam Public Health (NL)
- Université de Sherbrooke (CA)
- University College London (GB)
- Imperial College London (GB)
- Translational Research Institute (AU)
- University of Helsinki (FI)
- Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, the Netherlands54Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
- University of Potsdam (DE)
- Sahlgrenska University Hospital (SE)
- University of Copenhagen (DK)
- EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands22Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands
- Oulu University Hospital (FI)
- University of Southern Denmark (DK)
- University of Iowa (US)
- School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, United Kingdom5Medical Research Council Integrative Epidemiology Unit at the University of Bristol, United Kingdom
- University of South Australia (AU)
- Corresponding author
- Lawlor, Debbie A.
- Freathy, Rachel M.
- ORCID
- Tyrrell, Jessica
- Richmond, Rebecca C.
- Palmer, Tom M.
- Feenstra, Bjarke
- Metrustry, Sarah
- Cavadino, Alana
- Paternoster, Lavinia
- Wood, Andrew R.
- Horikoshi, Momoko
- Geller, Frank
- Myhre, Ronny
- Painter, Jodie N.
- Hottenga, Jouke-Jan
- Allard, Catherine
- Bouchard, Luigi
- Evans, David M.
- Hakonarson, Hakon
- Hayes, M. Geoffrey
- Heikkinen, Jani
- Knight, Bridget
- Lind, Penelope A.
- McCarthy, Mark I.
- Medland, Sarah E.
- Melbye, Mads
- Morris, Andrew P.
- Nodzenski, Michael
- Reichetzeder, Christoph
- Ring, Susan M.
- Sebert, Sylvain
- Sengpiel, Verena
- Sørensen, Thorkild I. A.
- Willemsen, Gonneke
- Martin, Nicholas G.
- Spector, Tim D.
- Power, Christine
- Järvelin, Marjo-Riitta
- Bisgaard, Hans
- Grant, Struan F. A.
- Nohr, Ellen A.
- Jaddoe, Vincent W.
- Jacobsson, Bo
- Murray, Jeffrey C.
- Hocher, Berthold
- Hattersley, Andrew T.
- Scholtens, Denise M.
- Hivert, Marie-France
- Felix, Janine F.
- Hyppönen, Elina
- Lowe, William L.
- Frayling, Timothy M.
- Lawlor, Debbie A.
- Freathy, Rachel M.
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2016-03-15
- Volume
- 315
- Issue
- 11
- Pages
- 1129
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC4811305
- OpenAlex
- W2296845877
- Cited by
- 284
- References
- 69
- Citations by year
- 2026: 18 · 2025: 23 · 2024: 18 · 2023: 32 · 2022: 33 · 2021: 27 · 2020: 27 · 2019: 31 · 2018: 24 · 2017: 28 · 2016: 23
- FWCI
- 40.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, other-oa)
- VU Research Portal (publishedVersion, other-oa)
- University of Southern Denmark Research Portal (University of Southern Denmark) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Open Research Exeter (University of Exeter) (acceptedVersion)
- Lancaster EPrints (Lancaster University) (submittedVersion)
- UniSA Research Outputs Repository (University of South Australia) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Figshare (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Juvenile Diabetes Research Foundation International (U01 DK062418)
- March of Dimes Foundation
- Massachusetts General Hospital
- Children's Hospital of Philadelphia
- University of Pennsylvania
- Canadian Diabetes Association
- Sundhed og Sygdom, Det Frie Forskningsråd
- South Australian Health and Medical Research Institute
- Université de Sherbrooke
- Wellcome Trust (098395, WT098017, 104150/Z/14/Z, WT083431MF, 102215, WT094529MA, 104150, WT088806)
- QIMR Berghofer Medical Research Institute
- National Institute for Health and Care Research (NF-SI-0611-10196, NF-SI-0611-10099, NF-SI-0611-10219, SI-0611-10196, NF-SI-0514-10027)
- Diabetes Research and Wellness Foundation
- British Heart Foundation
- Imperial College London
- University College London
- University of Oxford
- European Commission (633595)
- European Science Foundation
- University of Bristol
- National Research Foundation
- Deutsche Forschungsgemeinschaft
- Danmarks Grundforskningsfond
- University of South Australia
- ZonMw (VIDI 016. 136. 361, ZonMw-VIDI 016.136.361, 016.136.361)
- Erasmus Universiteit Rotterdam
- Vrije Universiteit Amsterdam
- Gentofte Hospital
- Erasmus Medisch Centrum
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Lundbeckfonden
- Jinan University
- Novo Nordisk
- Universität Potsdam
- Augustinus Fonden
- Norges Forskningsråd
- Oulun Yliopisto
- Syddansk Universitet
- Svenska Läkaresällskapet
- Faculty of Health and Medical Sciences, University of Western Australia
- Egmont Fonden
- Novo Nordisk Foundation Center for Basic Metabolic Research
- H. Lundbeck A/S
- Terveyden ja hyvinvoinnin laitos
- Centre for Medical Systems Biology
- Norwegian Biodiversity Information Centre
- National Institutes of Health
- School of Medicine, Stanford University
- Perelman School of Medicine, University of Pennsylvania
- Canadian Institutes of Health Research
- Fonds de Recherche du Québec - Santé
- Medical Research Council (MR/N01104X/1, MC_PC_15015, MC_UU_12011/5, FT130101709, MC_PC_15018, MR/J012165/1)
- Sahlgrenska Akademin
- Det Sundhedsvidenskabelige Fakultet, Københavns Universitet
- European Regional Development Fund
- Strategic Research Council
- Klinisk Institut, Syddansk Universitet
- Biocenter, University of Oulu
- Diamantina Institute, University of Queensland
- Norwegian Institute of Public Health
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK10324, DK062418, U01DK062418, R01DK103246)
- National Institute of Neurological Disorders and Stroke
- National Institute of Environmental Health Sciences (P30ES013508)
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD056465)
- Institute of Genetics
- Institute of Nutrition, Metabolism and Diabetes
- FP7 Ideas: European Research Council (323195)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- maternal obesity, body mass index, birth weight, causal inference, Mendelian randomization, maternal fasting glucose, type 2 diabetes, adiponectin, vitamin D status, HDL cholesterol, triglycerides, offspring growth, European ancestry women
- MeSH terms
- Adult, Birth Weight, Blood Glucose, Blood Pressure, Diabetes Mellitus, Type 2, Fasting, Female, Genotype, Humans, Infant, Newborn, Obesity, Pregnancy, Triglycerides, Body Mass Index, Polymorphism, Single Nucleotide, White People, Mendelian Randomization Analysis
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