title: Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: 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.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tyrrell
authors.affiliation: 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.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Richmond
authors.affiliation: Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom7Department of Mathematics and Statistics, Lancaster University, Lancaster, United Kingdom.
authors.forename: Tom M
authors.initials: TM
authors.lastname: Palmer
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Bjarke
authors.initials: B
authors.lastname: Feenstra
authors.affiliation: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Janani
authors.initials: J
authors.lastname: Rangarajan
authors.affiliation: Department of Twin Research, King's College London, St Thomas' Hospital, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Metrustry
authors.affiliation: 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.
authors.forename: Alana
authors.initials: A
authors.lastname: Cavadino
authors.affiliation: Medical Research Council Integrative Epidemiology Unit at the University of Bristol, United Kingdom.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Paternoster
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Loren L
authors.initials: LL
authors.lastname: Armstrong
authors.affiliation: Medical Research Council Integrative Epidemiology Unit at the University of Bristol, United Kingdom.
authors.forename: N Maneka G
authors.initials: NM
authors.lastname: De Silva
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Wood
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, United Kingdom15Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Momoko
authors.initials: M
authors.lastname: Horikoshi
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Frank
authors.initials: F
authors.lastname: Geller
authors.affiliation: Division of Epidemiology, Department of Genes and Environment, Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Ronny
authors.initials: R
authors.lastname: Myhre
authors.affiliation: Center for Applied Genomics, the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Bradfield
authors.affiliation: 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.
authors.forename: Eskil
authors.initials: E
authors.lastname: Kreiner-Møller
authors.affiliation: Institute of Health Sciences, University of Oulu, Oulu, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Huikari
authors.affiliation: QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, Australia.
authors.forename: Jodie N
authors.initials: JN
authors.lastname: Painter
authors.affiliation: EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands22Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jouke-Jan
authors.initials: JJ
authors.lastname: Hottenga
authors.affiliation: Department of Mathematics, Universite de Sherbrooke, Quebec City, Quebec, Canada24Centre de recherché du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec City, Quebec, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Allard
authors.affiliation: Population, Policy and Practice, UCL Institute of Child Health, University College London, United Kingdom.
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Berry
authors.affiliation: 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.
authors.forename: Luigi
authors.initials: L
authors.lastname: Bouchard
authors.affiliation: Department of Primary Care and Public Health, Imperial College London, United Kingdom.
authors.forename: Shikta
authors.initials: S
authors.lastname: Das
authors.affiliation: 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.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.affiliation: 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.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: M Geoffrey
authors.initials: MG
authors.lastname: Hayes
authors.affiliation: FIMM Institute for Molecular Medicine Finland, Helsinki University, Helsinki, Finland.
authors.forename: Jani
authors.initials: J
authors.lastname: Heikkinen
authors.affiliation: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, the Netherlands54Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, United Kingdom.
authors.forename: Bridget
authors.initials: B
authors.lastname: Knight
authors.affiliation: QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, Australia.
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Lind
authors.affiliation: 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.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: McMahon
authors.affiliation: QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, Australia.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Medland
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark34Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: Mads
authors.initials: M
authors.lastname: Melbye
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom35Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Morris
authors.affiliation: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Michael
authors.initials: M
authors.lastname: Nodzenski
authors.affiliation: Institute of Nutritional Science, University of Potsdam, Germany37Center for Cardiovascular Research/Charité, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Reichetzeder
authors.affiliation: 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.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.affiliation: 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.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Sebert
authors.affiliation: Department of Obstetrics and Gynecology, Sahlgrenska Academy, Sahgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Verena
authors.initials: V
authors.lastname: Sengpiel
authors.affiliation: 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.
authors.forename: Thorkild I A
authors.initials: TI
authors.lastname: Sørensen
authors.affiliation: EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands22Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands.
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.affiliation: EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands22Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands.
authors.forename: Eco J C
authors.initials: EJ
authors.lastname: de Geus
authors.affiliation: QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Department of Twin Research, King's College London, St Thomas' Hospital, London, United Kingdom.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Population, Policy and Practice, UCL Institute of Child Health, University College London, United Kingdom.
authors.forename: Christine
authors.initials: C
authors.lastname: Power
authors.affiliation: 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.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.affiliation: 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.
authors.forename: Hans
authors.initials: H
authors.lastname: Bisgaard
authors.affiliation: 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.
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
authors.affiliation: Research Unit of Obstetrics & Gynecology, Institute of Clinical Research, University of Southern Denmark, Odense.
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Nohr
authors.affiliation: 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.
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Jaddoe
authors.affiliation: 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.
authors.forename: Bo
authors.initials: B
authors.lastname: Jacobsson
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.affiliation: Institute of Nutritional Science, University of Potsdam, Germany48The First Affiliated Hospital of Jinan University, Guangzhou, China.
authors.forename: Berthold
authors.initials: B
authors.lastname: Hocher
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, United Kingdom.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.affiliation: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Scholtens
authors.affiliation: 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.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: 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.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Hivert
authors.affiliation: 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.
authors.forename: Janine F
authors.initials: JF
authors.lastname: Felix
authors.affiliation: 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.
authors.forename: Elina
authors.initials: E
authors.lastname: Hyppönen
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: William L
authors.initials: WL
authors.lastname: Lowe
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, United Kingdom.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.affiliation: 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.
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.affiliation: 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.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Freathy
mesh_terms: D000328:Adult; D001724:Birth Weight / Q000235:genetics*; D001786:Blood Glucose / Q000235:genetics*; D001794:Blood Pressure / Q000235:genetics; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005215:Fasting / Q000097:blood*; D005260:Female; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D057182:Mendelian Randomization Analysis; D009765:Obesity / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D014280:Triglycerides / Q000235:genetics; D044465:White People
chemical_list: D001786:Blood Glucose; D014280:Triglycerides