Jessica Tyrrell1, Rebecca C Richmond2, Tom M Palmer3, Bjarke Feenstra4, Janani Rangarajan5, Sarah Metrustry6, Alana Cavadino7, Lavinia Paternoster8, Loren L Armstrong9, N Maneka G De Silva8, Andrew R Wood10, Momoko Horikoshi11, Frank Geller4, Ronny Myhre12, Jonathan P Bradfield13, Eskil Kreiner-Møller14, Ville Huikari15, Jodie N Painter16, Jouke-Jan Hottenga17, Catherine Allard18, Diane J Berry19, Luigi Bouchard20, Shikta Das21, David M Evans22, Hakon Hakonarson23, M Geoffrey Hayes9, Jani Heikkinen24, Albert Hofman25, Bridget Knight10, Penelope A Lind16, Mark I McCarthy26, George McMahon27, Sarah E Medland16, Mads Melbye28, Andrew P Morris29, Michael Nodzenski5, Christoph Reichetzeder30, Susan M Ring31, Sylvain Sebert32, Verena Sengpiel33, Thorkild I A Sørensen34, Gonneke Willemsen17, Eco J C de Geus17, Nicholas G Martin16, Tim D Spector6, Christine Power19, Marjo-Riitta Järvelin32, Hans Bisgaard14, Struan F A Grant23, Ellen A Nohr35, Vincent W Jaddoe36, Bo Jacobsson37, Jeffrey C Murray38, Berthold Hocher39, Andrew T Hattersley10, Denise M Scholtens5, George Davey Smith31, Marie-France Hivert40, Janine F Felix36, Elina Hyppönen41, William L Lowe9, Timothy M Frayling10, Debbie A Lawlor31, Rachel M Freathy42. 1. Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, United Kingdom2European Centre for Environment and Human Health, University of Exeter, the Knowledge Spa, Truro, United Kingdom. 2. School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, United Kingdom4The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands5Medical Research Council Inte. 3. Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom7Department of Mathematics and Statistics, Lancaster University, Lancaster, United Kingdom. 4. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. 5. Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 6. Department of Twin Research, King's College London, St Thomas' Hospital, London, United Kingdom. 7. Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Barts, and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom12Population, Policy and Practice, UCL Institute of Child He. 8. Medical Research Council Integrative Epidemiology Unit at the University of Bristol, United Kingdom. 9. Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 10. Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, United Kingdom. 11. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, United Kingdom15Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. 12. Division of Epidemiology, Department of Genes and Environment, Norwegian Institute of Public Health, Oslo, Norway. 13. Center for Applied Genomics, the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 14. 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. 15. Institute of Health Sciences, University of Oulu, Oulu, Finland. 16. QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, Australia. 17. EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands22Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands. 18. Department of Mathematics, Universite de Sherbrooke, Quebec City, Quebec, Canada24Centre de recherché du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec City, Quebec, Canada. 19. Population, Policy and Practice, UCL Institute of Child Health, University College London, United Kingdom. 20. Centre de recherché du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec City, Quebec, Canada25ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, Quebec City, Quebec, Canada26Department of Biochemistry, Université de Sherbrooke. 21. Department of Primary Care and Public Health, Imperial College London, United Kingdom. 22. 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 Kingdom28University of Queensland Diamantin. 23. Center for Applied Genomics, the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania29Division of Human Genetics, the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania30Department of Pediatrics, Perelman School of Medicine, Unive. 24. FIMM Institute for Molecular Medicine Finland, Helsinki University, Helsinki, Finland. 25. Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, the Netherlands54Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. 26. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, United Kingdom15Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom33Oxford National Institute for Health Research (NIHR) Biomedical Researc. 27. School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, United Kingdom. 28. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark34Department of Medicine, Stanford University School of Medicine, Stanford, California. 29. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom35Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom. 30. Institute of Nutritional Science, University of Potsdam, Germany37Center for Cardiovascular Research/Charité, Berlin, Germany. 31. 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. 32. Institute of Health Sciences, University of Oulu, Oulu, Finland38Department of Epidemiology and Biostatistics, School of Public Health, Medical Research Council-Health Protection Agency Centre for Environment and Health, Faculty of Medicine, Imperial Coll. 33. Department of Obstetrics and Gynecology, Sahlgrenska Academy, Sahgrenska University Hospital, Gothenburg, Sweden. 34. Medical Research Council Integrative Epidemiology Unit at the University of Bristol, United Kingdom40Institute of Preventive Medicine, Bispebjerg and Frederiksberg University Hospital, Capital Region, Copenhagen, Denmark41Novo Nordisk Foundation Center fo. 35. Research Unit of Obstetrics & Gynecology, Institute of Clinical Research, University of Southern Denmark, Odense. 36. The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands32Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, the Netherlands46Department of Pediatrics, Erasmus MC, University Medic. 37. Division of Epidemiology, Department of Genes and Environment, Norwegian Institute of Public Health, Oslo, Norway39Department of Obstetrics and Gynecology, Sahlgrenska Academy, Sahgrenska University Hospital, Gothenburg, Sweden. 38. Department of Pediatrics, University of Iowa, Iowa City. 39. Institute of Nutritional Science, University of Potsdam, Germany48The First Affiliated Hospital of Jinan University, Guangzhou, China. 40. Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, Massachusetts50Diabetes Center, Massachusetts General Hospital, Boston51Department of Medicine, Universite de Sherbrooke, Quebec City, Quebec, Canada. 41. Population, Policy and Practice, UCL Institute of Child Health, University College London, United Kingdom52Centre for Population Health Research, School of Health Sciences, and Sansom Institute, University of South Australia, Adelaide53South Australian He. 42. Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, United Kingdom5Medical Research Council Integrative Epidemiology Unit at the University of Bristol, United Kingdom.
Abstract
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.
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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