Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
29309628
TITLE
Genome-wide association study of offspring birth weight in 86?577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.
ABSTRACT
Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
© The Author(s) 2018. Published by Oxford University Press.
DATE PUBLISHED
2018 02 15
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2017/11/02
accepted 2017/12/15
pubmed 2018/01/09 06:00
medline 2019/01/08 06:00
entrez 2018/01/09 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Beaumont RN Beaumont Robin N RN Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Exeter EX2 5DW, UK.
Warrington NM Warrington Nicole M NM Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, QLD, Australia.
Cavadino A Cavadino Alana A 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, London, UK.
Tyrrell J Tyrrell Jessica J European Centre for Environment and Human Health, University of Exeter, The Knowledge Spa, Truro TR1 3HD, UK.
Nodzenski M Nodzenski Michael M Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Horikoshi M Horikoshi Momoko M Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Geller F Geller Frank F Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Myhre R Myhre Ronny R Division of Epidemiology, Department of Genes and Environment, Norwegian Institute of Public Health, Oslo, Norway.
Richmond RC Richmond Rebecca C RC The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands.
Paternoster L Paternoster Lavinia L Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
Bradfield JP Bradfield Jonathan P JP Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Kreiner-Møller E Kreiner-Møller Eskil E Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.
Huikari V Huikari Ville V Institute of Health Sciences, University of Oulu, Oulu, Finland.
Metrustry S Metrustry Sarah S Department of Twin Research, King's College London, St. Thomas' Hospital, London, UK.
Lunetta KL Lunetta Kathryn L KL Framingham Heart Study, Framingham, MA, USA.
Painter JN Painter Jodie N JN QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, QLD 4029, Australia.
Hottenga JJ Hottenga Jouke-Jan JJ Department of Biological Psychology, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands.
Allard C Allard Catherine C Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
Barton SJ Barton Sheila J SJ Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
Espinosa A Espinosa Ana A ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
Marsh JA Marsh Julie A JA Division of Obstetrics and Gynaecology, The University of Western Australia, Perth, Australia.
Potter C Potter Catherine C Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
Zhang G Zhang Ge G March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, OH, USA.
Ang W Ang Wei W Division of Obstetrics and Gynaecology, The University of Western Australia, Perth, Australia.
Berry DJ Berry Diane J DJ Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
Bouchard L Bouchard Luigi L Department of Biochemistry, Université de Sherbrooke, Sherbrooke, QC, Canada.
Das S Das Shikta S Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
Early Growth Genetics (EGG) Consortium
Hakonarson H Hakonarson Hakon H Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Heikkinen J Heikkinen Jani J FIMM Institute for Molecular Medicine Finland, Helsinki University, Helsinki FI-00014, Finland.
Helgeland Ø Helgeland Øyvind Ø Department of Genetics and Bioinformatics, Domain of Health Data and Digitalisation, Institute of Public Health, Oslo, Norway.
Hocher B Hocher Berthold B Institute of Nutritional Science, University of Potsdam, Potsdam, Germany.
Hofman A Hofman Albert A Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands.
Inskip HM Inskip Hazel M HM NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK.
Jones SE Jones Samuel E SE Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Exeter EX2 5DW, UK.
Kogevinas M Kogevinas Manolis M ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
Lind PA Lind Penelope A PA QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, QLD 4029, Australia.
Marullo L Marullo Letizia L Genetic Section, Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
Medland SE Medland Sarah E SE QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, QLD 4029, Australia.
Murray A Murray Anna A Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Exeter EX2 5DW, UK.
Murray JC Murray Jeffrey C JC Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
Njølstad PR Njølstad Pål R PR Department of Pediatrics, Haukeland University Hospital, Bergen 5021, Norway.
Nohr EA Nohr Ellen A EA Research Unit of Obstetrics & Gynecology, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
Reichetzeder C Reichetzeder Christoph C Center for Cardiovascular Research, Charité, Berlin, Germany.
Ring SM Ring Susan M SM Population Health Science, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
Ruth KS Ruth Katherine S KS Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Exeter EX2 5DW, UK.
Santa-Marina L Santa-Marina Loreto L Instituto de Investigación Sanitaria BIODONOSTIA, Donostia/San Sebastián, Spain.
Scholtens DM Scholtens Denise M DM Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Sebert S Sebert Sylvain S Department of Epidemiology and Biostatistics, School of Public Health, Medical Research Council-Health Protection Agency Centre for Environment and Health, Faculty of Medicine, Imperial College London, London, UK.
Sengpiel V Sengpiel Verena V Department of Obstetrics and Gynecology, Sahlgrenska Academy, Sahgrenska University Hospital, Gothenburg, Sweden.
Tuke MA Tuke Marcus A MA Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Exeter EX2 5DW, UK.
Vaudel M Vaudel Marc M Department of Clinical Science, KG Jebsen Center for Diabetes Research, University of Bergen, Bergen, Norway.
Weedon MN Weedon Michael N MN Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Exeter EX2 5DW, UK.
Willemsen G Willemsen Gonneke G Department of Biological Psychology, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands.
Wood AR Wood Andrew R AR Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Exeter EX2 5DW, UK.
Yaghootkar H Yaghootkar Hanieh H Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Exeter EX2 5DW, UK.
Muglia LJ Muglia Louis J LJ March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, OH, USA.
Bartels M Bartels Meike M Department of Biological Psychology, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands.
Relton CL Relton Caroline L CL Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
Pennell CE Pennell Craig E CE Division of Obstetrics and Gynaecology, The University of Western Australia, Perth, Australia.
Chatzi L Chatzi Leda L Department of Social Medicine, University of Crete, Crete, Greece.
Estivill X Estivill Xavier X ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
Holloway JW Holloway John W JW Human Development & Health, Faculty of Medicine, University of Southampton, Southampton, UK.
Boomsma DI Boomsma Dorret I DI Department of Biological Psychology, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands.
Montgomery GW Montgomery Grant W GW QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, QLD 4029, Australia.
Murabito JM Murabito Joanne M JM Section of General Internal Medicine, Boston University School of Medicine, Boston, MA, USA.
Spector TD Spector Tim D TD Department of Twin Research, King's College London, St. Thomas' Hospital, London, UK.
Power C Power Christine C Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
Järvelin MR Järvelin Marjo-Ritta MR Department of Children and Young People and Families, National Institute for Health and Welfare, FI-90101 Oulu, Finland.
Bisgaard H Bisgaard Hans H Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.
Grant SFA Grant Struan F A SFA Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Sørensen TIA Sørensen Thorkild I A TIA Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Jaddoe VW Jaddoe Vincent W VW Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands.
Jacobsson B Jacobsson Bo B Department of Obstetrics and Gynecology, Sahlgrenska Academy, Sahgrenska University Hospital, Gothenburg, Sweden.
Melbye M Melbye Mads M Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
McCarthy MI McCarthy Mark I MI Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Oxford, UK.
Hattersley AT Hattersley Andrew T AT Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Exeter EX2 5DW, UK.
Hayes MG Hayes M Geoffrey MG Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Frayling TM Frayling Timothy M TM Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Exeter EX2 5DW, UK.
Hivert MF Hivert Marie-France MF Department of Medicine, Universite de Sherbrooke, QC, Canada.
Felix JF Felix Janine F JF Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands.
Hyppönen E Hyppönen Elina E South Australian Health and Medical Research Institute, Adelaide, Australia.
Lowe WL Jr Lowe William L WL Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Evans DM Evans David M DM Population Health Science, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
Lawlor DA Lawlor Debbie A DA Population Health Science, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
Feenstra B Feenstra Bjarke B Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Freathy RM Freathy Rachel M RM Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
INVESTIGATORS
JOURNAL
VOLUME: 27
ISSUE: 4
TITLE: Human molecular genetics
ISOABBREVIATION: Hum Mol Genet
YEAR: 2018
MONTH: 02
DAY: 15
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1460-2083
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Hum Mol Genet
COUNTRY: England
ISSNLINKING: 0964-6906
NLMUNIQUEID: 9208958
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
GRANTS
GRANTID AGENCY COUNTRY
G1001799 Medical Research Council United Kingdom
RG/15/17/31749 British Heart Foundation United Kingdom
R01 DK077659 NIDDK NIH HHS United States
MR/N01104X/2 Medical Research Council United Kingdom
MC_QA137853 Medical Research Council United Kingdom
G0601653 Medical Research Council United Kingdom
104150 Wellcome Trust United Kingdom
MR/N01104X/1 Medical Research Council United Kingdom
MC_UU_12013/4 Medical Research Council United Kingdom
R01 DK103246 NIDDK NIH HHS United States
Wellcome Trust United Kingdom
MC_UU_12011/4 Medical Research Council United Kingdom
PG/09/023/26806 British Heart Foundation United Kingdom
MC_UU_12013/5 Medical Research Council United Kingdom
MC_UU_12013/2 Medical Research Council United Kingdom
PHCS/C4/4/016 Department of Health United Kingdom
P30 ES013508 NIEHS NIH HHS United States
648916 European Research Council International
R01 AG029451 NIA NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Actins genetics
Adaptor Proteins, Signal Transducing genetics
Alleles genetics
Birth Weight physiology
Cytochrome P-450 CYP3A genetics
DNA-Binding Proteins genetics
Female genetics
Genetic Variation genetics
Genome-Wide Association Study methods
Genotype methods
Germinal Center Kinases methods
Gestational Age methods
HMGA2 Protein genetics
Humans genetics
Intracellular Signaling Peptides and Proteins genetics
Kv1.3 Potassium Channel genetics
Polymorphism, Single Nucleotide genetics
Protein-Serine-Threonine Kinases genetics
Proteins genetics
Receptor, Melatonin, MT2 genetics
Trans-Activators genetics
Transcription Factor 7-Like 2 Protein genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 ACTL9 protein, human
0 Actins
0 Adaptor Proteins, Signal Transducing
0 DNA-Binding Proteins
0 EBF1 protein, human
0 Germinal Center Kinases
0 HMGA2 Protein
0 HMGA2 protein, human
0 Intracellular Signaling Peptides and Proteins
0 KCNAB1 protein, human
0 Kv1.3 Potassium Channel
0 L3MBTL3 protein, human
0 MTNR1B protein, human
0 Proteins
0 Receptor, Melatonin, MT2
0 SH2B3 protein, human
0 Trans-Activators
0 Transcription Factor 7-Like 2 Protein
EC 1.14.14.1 CYP3A7 protein, human
EC 1.14.14.1 Cytochrome P-450 CYP3A
EC 2.7.11.1 Protein-Serine-Threonine Kinases
OTHER ID's
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