Authors

Robin N Beaumont, University of Exeter
Nicole M Warrington, University of Queensland
Alana Cavadino, Wolfson Institute of Preventative Medicine
Jessica Tyrrell, University of Exeter
Michael Nodzenski, Northwestern University
Momoko Horikoshi, University of Oxford
Frank Geller, Statens Serum Institut
Ronny Myhre, Norwegian Instite of Public Health
Rebecca C Richmond, University of Bristol
Lavinia Paternoster, University of Bristol
Jonathan P. Bradfield, The Children’s Hospital of Philadelphia
Eskil Kreiner-Møller, University of Copenhagen
Ville Huikari, University of Oulu
Sarah Metrustry, King’s College London
Kathryn L. Lunetta, Boston University
Jodie N. Painter, Royal Brisbane Hospital
Jouke-Jan Hottenga, Vrije Universiteit Amsterdam
Catherine Allard, Universitaire de Sherbrooke
Sheila J. Barton, University of Southampton
Ana Espinosa, Pompeu Fabra University
Julie A. Marsh, University of Western Australia
Catherine Potter, Newcastle University
Ge Zhang, Cincinnati Children’s Hospital Medical Center
Wei Ang, University of Western Australia
Diane J. Berry, University College London
Luigi Bouchard, Universitaire de Sherbrooke
Shikta Das, University College London
Early Growth Genetics (EGG) Consortium
Hakon Hakonarson, The Children’s Hospital of Philadelphia
Jani Heikkinen, Helsinki University
Øyvind Helgeland, University of Bergen
Berthold Hocher, Jinan University - China
Albert Hofman, University Medical Center Rotterdam
Hazel M Inskip, University of Southampton
Samuel E Jones, University of Exeter
Manolis Kogevinas, Pompeu Fabra University
Penelope A Lind, Royal Brisbane Hospital
Letizia Marullo, University of Ferrara
Sarah E Medland, Royal Brisbane Hospital
Anna Murray, University of Exeter
Jeffrey C Murray, University of IowaFollow
Pål R Njølstad, Helsinki University
Ellen A Nohr, University of Southern Denmark
Christoph Reichetzeder, University of Potsdam
Susan M Ring, University of Bristol
Katherine S Ruth, University of Exeter
Loreto Santa-Marina, Centre for Research in Environmental Epidemiology
Denise M Scholtens, Northwestern University
Sylvain Sebert, University of Oulu
Verena Sengpiel, Sahgrenska University
Marcus A Tuke, University of Exeter
Marc Vaudel, University of Bergen
Michael N Weedon, University of Exeter
Gonneke Willemsen, Vrije Universiteit Amsterdam
Andrew R Wood, University of Exeter
Hanieh Yaghootkar, University of Exeter
Louis J Muglia, Cincinnati Children’s Hospital Medical Center
Meike Bartels, Vrije Universiteit Amsterdam
Caroline L Relton, University of Bristol
Craig E Pennell, University of Western Australia
Leda Chatzi, University of Crete
Xavier Estivill, Pompeu Fabra University
John W Holloway, University of Southampton
Dorret I Boomsma, Vrije Universiteit Amsterdam
Grant W Montgomery, Royal Brisbane Hospital
Joanne M Murabito, Boston University
Tim D Spector, King’s College London
Christine Power, University College London
Marjo-Ritta Järvelin, University of Oulu
Hans Bisgaard, University of Copenhagen
Struan F.A. Grant, The Children’s Hospital of Philadelphia
Thorkild I.A. Sørensen, University of Bristol
Vincent W Jaddoe, University Medical Center Rotterdam
Bo Jacobsson, Norwegian Institute of Public Health
Mads Melbye, Statens Serum Institut
Mark I McCarthy, University of Oxford
Andrew T Hattersley, University of Exeter
M Geoffery Hayes, Northwestern University
Timothy M Frayling, University of Exeter
Marie-France Hivert, Harvard Medical School
Janine F Felix, University Medical Center Rotterdam
Elina Hyppönen, University College London
William L Lowe Jr., Northwestern University
David M Evans, University of Queensland
Debbie A Lawlor, University of Bristol
Bjarke Feenstra, Statens Serum Institut
Rachel M Freathy, University of Exeter

Document Type

Article

Peer Reviewed

1

Publication Date

2-15-2018

NLM Title Abbreviation

Hum Mol Genet

Journal/Book/Conference Title

Human molecular genetics

PubMed ID

29309628

DOI of Published Version

10.1093/hmg/ddx429

Start Page

742

End Page

756

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.

Keywords

pediactrics, cytochrome P450 3A7, high mobility group A2 protein, sex hormone, transcription factor 7 like 2, ACTL9 gene, allele, diet restriction, EBF1 gene, fetus growth, GCK gene, gene locus, genome-wide association study, genotype, glucose blood level, heredity, high birth weight, human experiment, KCNAB1 gene, L3MBTL3 gene, low birth weight, MTNR1B gene, priority journal, progeny, SH2B3 gene, single nucleotide polymorphism, uterus

Comments

Researchers were funded by investment from the European Regional Development Fund (ERDF) and the European Social Fund (ESF) Convergence Programme for Cornwall and the Isles of Scilly [J.T.]; European Research Council (ERC) [grant: SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC to T.M.F., A.R.W.], [ERC Consolidator Grant, ERC-2014-CoG-648916 to V.W.V.J.], [P.R.N.]; University of Bergen, KG Jebsen and Helse Vest [P.R.N.]; Wellcome Trust Senior Investigator Awards [A.T.H. (WT098395), M.I.M. (WT098381)]; National Institute for Health Research (NIHR) Senior Investigator Award (NF-SI-0611–10219); Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150) [R.M.F., R.N.B.]; 4-year studentship (Grant Code: WT083431MF) [R.C.R]; the European Research Council under the European Union’s Seventh Framework Programme (FP/2007– 2013)/ERC Grant Agreement (grant number 669545; Develop Obese) [D.A.L.]; US National Institute of Health (grant: R01 DK10324) [D.A.L, C.L.R]; Wellcome Trust GWAS grant (WT088806) [D.A.L] and NIHR Senior Investigator Award (NF-SI- 0611–10196) [D.A.L]; Wellcome Trust Institutional Strategic Support Award (WT097835MF) [M.A.T.]; The Diabetes Research and Wellness Foundation Non-Clinical Fellowship [J.T.]; Australian National Health and Medical Research Council Early Career Fellowship (APP1104818) [N.M.W.]; Daniel B. Burke Endowed Chair for Diabetes Research [S.F.A.G.]; UK Medical Research Council Unit grants MC_UU_12013_5 [R.C.R, L.P, S.R, C.L.R, D.M.E., D.A.L.] and MC_UU_12013_4 [D.M.E.]; Medical Research Council (grant: MR/M005070/1) [M.N.W., S.E.J.]; Australian Research Council Future Fellowship (FT130101709) [D.M.E] and (FT110100548) [S.E.M.]; NIHR Oxford Biomedical Research Centre (BRC); Oak Foundation Fellowship and Novo Nordisk Foundation (12955) [B.F.]; FRQS research scholar and Clinical Scientist Award by the Canadian Diabetes Association and the Maud Menten Award from the Institute of Genetics– Canadian Institute of Health Research (CIHR) [MFH]; CIHR— Frederick Banting and Charles Best Canada Graduate Scholarships [C.A.]; FRQS [L.B.]; Netherlands Organization for Health Research and Development (ZonMw–VIDI 016.136.361) [V.W.V.J.]; National Institute on Aging (R01AG29451) [J.M.M.]; 2010–2011 PRIN funds of the University of Ferrara—Holder: Prof. Guido Barbujani, Supervisor: Prof. Chiara Scapoli—and in part sponsored by the European Foundation for the Study of Diabetes (EFSD) Albert Renold Travel Fellowships for Young Scientists, ‘5 per mille’ contribution assigned to the University of Ferrara, income tax return year 2009 and the ENGAGE Exchange and Mobility Program for ENGAGE training funds, ENGAGE project, grant agreement HEALTH-F4–2007-201413 [L.M.]; ESRC (RES-060–23-0011) [C.L.R.]; National Institute of Health Research ([S.D., M.I.M.], Senior Investigator Award (NFSI- 0611–10196) [D.A.L]); Australian NHMRC Fellowships Scheme (619667) [G.W.M].

Journal Article Version

Version of Record

Published Article/Book Citation

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

Rights

© The Author(s) 2018

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

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URL

https://ir.uiowa.edu/pediatrics_pubs/22