Journal article
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
Human molecular genetics, Vol.27(4), pp.742-756
02/15/2018
DOI: 10.1093/hmg/ddx429
PMCID: PMC5886200
PMID: 29309628
Abstract
<p>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.</p>
Details
- Title: Subtitle
- 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
- Creators
- Robin N Beaumont - University of ExeterNicole M Warrington - University of QueenslandAlana Cavadino - Wolfson Institute of Preventative MedicineJessica Tyrrell - University of ExeterMichael Nodzenski - Northwestern UniversityMomoko Horikoshi - University of OxfordFrank Geller - Statens Serum InstitutRonny Myhre - Norwegian Instite of Public HealthRebecca C Richmond - University of BristolLavinia Paternoster - University of BristolJonathan P. Bradfield - The Children’s Hospital of PhiladelphiaEskil Kreiner-Møller - University of CopenhagenVille Huikari - University of OuluSarah Metrustry - King’s College LondonKathryn L. Lunetta - Boston UniversityJodie N. Painter - Royal Brisbane HospitalJouke-Jan Hottenga - Vrije Universiteit AmsterdamCatherine Allard - Universitaire de SherbrookeSheila J. Barton - University of SouthamptonAna Espinosa - Pompeu Fabra UniversityJulie A. Marsh - University of Western AustraliaCatherine Potter - Newcastle UniversityGe Zhang - Cincinnati Children’s Hospital Medical CenterWei Ang - University of Western AustraliaDiane J. Berry - University College LondonLuigi Bouchard - Universitaire de SherbrookeShikta Das - University College LondonEarly Growth Genetics (EGG) ConsortiumHakon Hakonarson - The Children’s Hospital of PhiladelphiaJani Heikkinen - Helsinki UniversityØyvind Helgeland - University of BergenBerthold Hocher - Jinan University - ChinaAlbert Hofman - University Medical Center RotterdamHazel M Inskip - University of SouthamptonSamuel E Jones - University of ExeterManolis Kogevinas - Pompeu Fabra UniversityPenelope A Lind - Royal Brisbane HospitalLetizia Marullo - University of FerraraSarah E Medland - Royal Brisbane HospitalAnna Murray - University of ExeterJeffrey C Murray - University of IowaPål R Njølstad - Helsinki UniversityEllen A Nohr - University of Southern DenmarkChristoph Reichetzeder - University of PotsdamSusan M Ring - University of BristolKatherine S Ruth - University of ExeterLoreto Santa-Marina - Centre for Research in Environmental EpidemiologyDenise M Scholtens - Northwestern UniversitySylvain Sebert - University of OuluVerena Sengpiel - Sahgrenska UniversityMarcus A Tuke - University of ExeterMarc Vaudel - University of BergenMichael N Weedon - University of ExeterGonneke Willemsen - Vrije Universiteit AmsterdamAndrew R Wood - University of ExeterHanieh Yaghootkar - University of ExeterLouis J Muglia - Cincinnati Children’s Hospital Medical CenterMeike Bartels - Vrije Universiteit AmsterdamCaroline L Relton - University of BristolCraig E Pennell - University of Western AustraliaLeda Chatzi - University of CreteXavier Estivill - Pompeu Fabra UniversityJohn W Holloway - University of SouthamptonDorret I Boomsma - Vrije Universiteit AmsterdamGrant W Montgomery - Royal Brisbane HospitalJoanne M Murabito - Boston UniversityTim D SpectorChristine Power - University College LondonMarjo-Ritta Järvelin - University of OuluHans Bisgaard - University of CopenhagenStruan F.A. Grant - The Children’s Hospital of PhiladelphiaThorkild I.A. Sørensen - University of BristolVincent W Jaddoe - University Medical Center RotterdamBo Jacobsson - Norwegian Institute of Public HealthMads Melbye - Statens Serum InstitutMark I McCarthy - University of OxfordAndrew T Hattersley - University of ExeterM Geoffery Hayes - Northwestern UniversityTimothy M Frayling - University of ExeterMarie-France Hivert - Harvard Medical SchoolJanine F Felix - University Medical Center RotterdamElina Hyppönen - University College LondonWilliam L Lowe Jr. - Northwestern UniversityDavid M Evans - University of QueenslandDebbie A Lawlor - University of BristolBjarke Feenstra - Statens Serum InstitutRachel M Freathy - University of Exeter
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.27(4), pp.742-756
- DOI
- 10.1093/hmg/ddx429
- PMID
- 29309628
- PMCID
- PMC5886200
- NLM abbreviation
- Hum Mol Genet
- ISSN
- 1460-2083
- Publisher
- IRL Press at Oxford University Press
- Copyright
- © The Author(s) 2018
- Grant note
- 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].
- Language
- English
- Date published
- 02/15/2018
- Academic Unit
- Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Carver College of Medicine; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9983557794002771
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