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Hum Mol Genet. 2018 Feb 15;27(4):742-756. doi: 10.1093/hmg/ddx429.

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.

Author information

1
Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Exeter EX2 5DW, UK.
2
Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, QLD, Australia.
3
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.
4
European Centre for Environment and Human Health, University of Exeter, The Knowledge Spa, Truro TR1 3HD, UK.
5
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
6
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
7
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
8
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
9
Division of Epidemiology, Department of Genes and Environment, Norwegian Institute of Public Health, Oslo, Norway.
10
Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
11
Population Health Science, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
12
The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands.
13
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
14
Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
15
Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.
16
Institute of Health Sciences, University of Oulu, Oulu, Finland.
17
Department of Twin Research, King's College London, St. Thomas' Hospital, London, UK.
18
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
19
Framingham Heart Study, Framingham, MA, USA.
20
QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, QLD 4029, Australia.
21
EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.
22
Department of Biological Psychology, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands.
23
Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
24
Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
25
Pompeu Fabra University (UPF), Barcelona, Spain.
26
IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
27
ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
28
Division of Obstetrics and Gynaecology, The University of Western Australia, Perth, Australia.
29
Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
30
Human Genetics Division, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
31
Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center, OH, USA.
32
March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, OH, USA.
33
Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
34
ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, QC, Canada.
35
Department of Biochemistry, Université de Sherbrooke, Sherbrooke, QC, Canada.
36
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
37
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
38
FIMM Institute for Molecular Medicine Finland, Helsinki University, Helsinki FI-00014, Finland.
39
Department of Clinical Science, KG Jebsen Center for Diabetes Research, University of Bergen, Bergen, Norway.
40
Department of Genetics and Bioinformatics, Domain of Health Data and Digitalisation, Institute of Public Health, Oslo, Norway.
41
The First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
42
Institute of Nutritional Science, University of Potsdam, Potsdam, Germany.
43
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands.
44
NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK.
45
Genetic Section, Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
46
Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
47
Department of Pediatrics, Haukeland University Hospital, Bergen 5021, Norway.
48
Research Unit of Obstetrics & Gynecology, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
49
Center for Cardiovascular Research, Charité, Berlin, Germany.
50
Subdirección de Salud Pública y Adicciones de Gipuzkoa, Donostia/San Sebastián, Spain.
51
Instituto de Investigación Sanitaria BIODONOSTIA, Donostia/San Sebastián, Spain.
52
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.
53
Department of Obstetrics and Gynecology, Sahlgrenska Academy, Sahgrenska University Hospital, Gothenburg, Sweden.
54
Department of Social Medicine, University of Crete, Crete, Greece.
55
Human Development & Health, Faculty of Medicine, University of Southampton, Southampton, UK.
56
Section of General Internal Medicine, Boston University School of Medicine, Boston, MA, USA.
57
Biocenter Oulu, University of Oulu, Oulu, Finland.
58
Unit of Primary Care, Oulu University Hospital, FI-90220 Oulu, 90029 OYS, Finland.
59
Department of Children and Young People and Families, National Institute for Health and Welfare, FI-90101 Oulu, Finland.
60
Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
61
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
62
Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands.
63
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
64
Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Oxford, UK.
65
Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
66
Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA, USA.
67
Diabetes Center, Massachussetts General Hospital, Boston, MA, USA.
68
Department of Medicine, Universite de Sherbrooke, QC, Canada.
69
Centre for School of Population Health Research, School of Health Sciences, and Sansom Institute, University of South Australia, Adelaide, Australia.
70
South Australian Health and Medical Research Institute, Adelaide, Australia.

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.

PMID:
29309628
PMCID:
PMC5886200
DOI:
10.1093/hmg/ddx429
[Indexed for MEDLINE]
Free PMC Article

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