University of Oulu

Robin N Beaumont, Nicole M Warrington, Alana Cavadino, Jessica Tyrrell, Michael Nodzenski, Momoko Horikoshi, Frank Geller, Ronny Myhre, Rebecca C Richmond, Lavinia Paternoster, Jonathan P Bradfield, Eskil Kreiner-Møller, Ville Huikari, Sarah Metrustry, Kathryn L Lunetta, Jodie N Painter, Jouke-Jan Hottenga, Catherine Allard, Sheila J Barton, Ana Espinosa, Julie A Marsh, Catherine Potter, Ge Zhang, Wei Ang, Diane J Berry, Luigi Bouchard, Shikta Das, Early Growth Genetics (EGG) Consortium, Hakon Hakonarson, Jani Heikkinen, Øyvind Helgeland, Berthold Hocher, Albert Hofman, Hazel M Inskip, Samuel E Jones, Manolis Kogevinas, Penelope A Lind, Letizia Marullo, Sarah E Medland, Anna Murray, Jeffrey C Murray, Pål R Njølstad, Ellen A Nohr, Christoph Reichetzeder, Susan M Ring, Katherine S Ruth, Loreto Santa-Marina, Denise M Scholtens, Sylvain Sebert, Verena Sengpiel, Marcus A Tuke, Marc Vaudel, Michael N Weedon, Gonneke Willemsen, Andrew R Wood, Hanieh Yaghootkar, Louis J Muglia, Meike Bartels, Caroline L Relton, Craig E Pennell, Leda Chatzi, Xavier Estivill, John W Holloway, Dorret I Boomsma, Grant W Montgomery, Joanne M Murabito, Tim D Spector, Christine Power, Marjo-Ritta Järvelin, Hans Bisgaard, Struan F A Grant, Thorkild I A Sørensen, Vincent W Jaddoe, Bo Jacobsson, Mads Melbye, Mark I McCarthy, Andrew T Hattersley, M Geoffrey Hayes, Timothy M Frayling, Marie-France Hivert, Janine F Felix, Elina Hyppönen, William L Lowe, David M Evans, Debbie A Lawlor, Bjarke Feenstra, Rachel M Freathy; 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, Volume 27, Issue 4, 15 February 2018, Pages 742–756, https://doi.org/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

Saved in:
Author: Beaumont, Robin N.1; Warrington, Nicole M.2; Cavadino, Alana3;
Tyrrell, Jessica1,4; Nodzenski, Michael5; Horikoshi, Momoko6,7; Geller, Frank8; Myhre, Ronny9; Richmond, Rebecca C.10,11,12; Paternoster, Lavinia10; Bradfield, Jonathan P.13; Kreiner-Moller, Eskil14,15; Huikari, Ville16; Metrustry, Sarah17; Lunetta, Kathryn L.18,19; Painter, Jodie N.20; Hottenga, Jouke-Jan21,22; Allard, Catherine23; Barton, Sheila J.24; Espinosa, Ana25,26,27; Marsh, Julie A.28; Potter, Catherine29; Zhang, Ge30,31,32; Ang, Wei28; Berry, Diane J.33; Bouchard, Luigi23,34,35; Das, Shikta33; Hakonarson, Hakon13,36,37; Heikkinen, Jani38; Helgeland, Oyvind34,39,40; Hocher, Berthold41,42; Hofman, Albert43; Inskip, Hazel M.24,44,45; Jones, Samuel E.1; Kogevinas, Manolis25,26,27; Lind, Penelope A.20; Marullo, Letizia46; Medland, Sarah E.20; Murray, Anna1; Murray, Jeffrey C.47; Njolstad, Pal R.48,39; Nohr, Ellen A.49; Reichetzeder, Christoph42,50; Ring, Susan M.10,11; Ruth, Katherine S.1; Santa-Marina, Loreto27,51,52; Scholtens, Denise M.5; Sebert, Sylvain16,53; Sengpiel, Verena54; Tuke, Marcus A.1; Vaudel, Marc48; Weedon, Michael N.1; Willemsen, Gonneke21,22; Wood, Andrew R.1; Yaghootkar, Hanieh1; Muglia, Louis J.31,32; Bartels, Meike21,22; Relton, Caroline L.2,10,11,29; Pennell, Craig E.28; Chatzi, Leda55; Estivill, Xavier25,27; Holloway, John W.56; Boomsma, Dorret I.21,22; Montgomery, Grant W.20; Murabito, Joanne M.19,57; Spector, Tim D.17; Power, Christine33; Jarvelin, Marjo-Ritta16,53,58,59,60; Bisgaard, Hans14,15; Grant, Struan F. A.13,36,37; Sorensen, Thorkild I. A.10,61,62; Jaddoe, Vincent W.12,43,63; Jacobsson, Bo9,54; Melbye, Mads8,64; McCarthy, Mark I.6,7; Hattersley, Andrew T.1; Hayes, M. Geoffrey65; Frayling, Timothy M.1; Hivert, Marie-France66,67,68; Felix, Janine F.12,43,65; Hypponen, Elina33,69,70,71; Lowe, William L., Jr.65; Evans, David M.2,10,11; Lawlor, Debbie A.10,11; Feenstra, Bjarke8; Freathy, Rachel M.1,10
Organizations: 1Univ Exeter, Royal Devon & Exeter Hosp, Med Sch, Inst Biomed & Clin Sci, Exeter EX2 5DW, Devon, England.
2Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia.
3Queen Mary Univ London, Barts & London Sch Med & Dent, Wolfson Inst Prevent Med, Ctr Environm & Prevent Med, London, England.
4Univ Exeter, European Ctr Environm & Human Hlth, Knowledge Spa, Truro TR1 3HD, England.
5Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL USA.
6Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.
7Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
8Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark.
9Norwegian Inst Publ Hlth, Dept Genes & Environm, Div Epidemiol, Oslo, Norway.
10Univ Bristol, Med Res Council Integrat Epidemiol Unit, Oakfield House,Oakfield Rd, Bristol BS8 2BN, Avon, England.
11Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Oakfield House, Bristol BS8 2BN, Avon, England.
12Univ Med Ctr Rotterdam, Erasmus MC, Generat R Study Grp, NL-3000 CA Rotterdam, Netherlands.
13Childrens Hosp Philadelphia, Ctr Appl Gen, Philadelphia, PA USA.
14Univ Copenhagen, Fac Hlth Sci, Copenhagen Prospect Studies Asthma Childhood COPS, Copenhagen, Denmark.
15Copenhagen Univ Hosp, Danish Pediat Asthma Ctr, Gentofte, Denmark.
16Univ Oulu, Inst Hlth Sci, Oulu, Finland.
17St Thomas Hosp, Kings Coll London, Dept Twin Res, London, England.
18Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA.
19Framingham Heart Dis Epidemiol Study, Framingham, MA USA.
20Royal Brisbane Hosp, QIMR Berghofer Med Res Inst, Herston, Qld 4029, Australia.
21Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.
22Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands.
23Ctr Hosp Univ Sherbrooke, Ctr Rec, Sherbrooke, PQ, Canada.
24Univ Southampton, Med Res Council Lifecourse Epidemiol Unit, Southampton, Hants, England.
25Pompeu Fabra Univ UPF, Barcelona, Spain.
26IMIM Hosp Mar Med Res Inst, Barcelona, Spain.
27Ctr Res Environm Epidemiol CREAL, ISGlobal, Barcelona, Spain.
28Univ Western Australia, Dept Obstet & Gynaecol, Perth, WA, Australia.
29Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England.
30Cincinnati Childrens Hosp Med Ctr, Human Genet Div, Cincinnati, OH USA.
31Cincinnati Childrens Hosp Med Ctr, Perinatal Inst, Ctr Prevent Preterm Birth, Cincinnati, OH 45229 USA.
32March Dimes Prematur Res Ctr Ohio Collaborat, Cincinnati, OH USA.
33UCL, UCL Great Ormond St Inst Child Hlth, Populat Policy & Practice, London, England.
34Chicoutimi Hosp, ECOGENE & Lipid Clin 21, Saguenay, PQ, Canada.
35Univ Sherbrooke, Dept Biochem, Sherbrooke, PQ, Canada.
36Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA USA.
37Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA USA.
38Univ Helsinki, FIMM Inst Mol Med Finland, FI-00014 Helsinki, Finland.
39Haukeland Hosp, Dept Pediat, N-5021 Bergen, Norway.
40Inst Publ Hlth, Domain Hlth Data & Digitalisat, Dept Genet & Bioinformat, Oslo, Norway.
41Jinan Univ, Affiliated Hosp 1, Guangzhou 510630, Guangdong, Peoples R China.
42Univ Potsdam, Inst Nutr Sci, Potsdam, Germany.
43Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands.
44Univ Southampton, NIHR Southampton Biomed Res Ctr, Southampton, Hants, England.
45Univ Hosp Southampton NHS Fdn Trust, Southampton, Hants, England.
46Univ Ferrara, Dept Life Sci & Biotechnol, Genet Sect, Ferrara, Italy.
47Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA.
48Univ Bergen, KG Jebsen Ctr Diabet Res, Dept Clin Sci, Bergen, Norway.
49Univ Southern Denmark, Inst Clin Res, Res Unit Obstet & Gynecol, Odense, Denmark.
50Ctr Cardiovasc Res Charite, Berlin, Germany.
51Subdirecc Salud Publ & Adicc Gipuzkoa, Donostia San Sebastian, Spain.
52Inst Investigac Sanitaria BIOD, Donostia San Sebastian, Spain.
53Imperial Coll London, Med Res Council, Hlth Protect Agcy Ctr Environm & Hlth,Fac Med, Dept Epidemiol & Biostat,Sch Publ Hlth, London, England.
54Sahgrenska Univ Hosp, Sahlgrenska Acad, Dept Obstet & Gynecol, Gothenburg, Sweden.
55Univ Crete, Dept Social Med, Iraklion, Greece.
56Univ Southampton, Fac Med, Human Dev & Hlth, Southampton, Hants, England.
57Boston Univ, Sch Med, Sect Gen Internal Med, Boston, MA 02215 USA.
58Univ Oulu, Bioctr Oulu, Oulu, Finland.
59Oulu Univ Hosp, Unit Primary Care, FI-90220 Oulu, Oys, Finland.
60Natl Inst Hlth & Welf, Dept Children & Young People & Families, FI-90101 Oulu, Finland.
61Univ Copenhagen, Fac Hlth & Med Sci, Dept Publ Hlth, Copenhagen, Denmark.
62Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.
63Univ Med Ctr Rotterdam, Erasmus MC, Dept Pediat, NL-3000 CA Rotterdam, Netherlands.
64Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA.
65Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL USA.
66Harvard Med Sch, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA.
67Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA.
68Univ Sherbrooke, Dept Med, Sherbrooke, PQ, Canada.
69Univ South Australia, Sch Hlth Sci, Ctr Sch Populat Hlth Res, Adelaide, SA, Australia.
70Univ South Australia, Sansom Inst, Adelaide, SA, Australia.
71South Australian Hlth & Med Res Inst, Adelaide, SA, Australia.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.4 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe201804116465
Language: English
Published: Oxford University Press, 2018
Publish Date: 2018-04-11
Description:

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.

see all

Series: Human molecular genetics
ISSN: 0964-6906
ISSN-E: 1460-2083
ISSN-L: 0964-6906
Volume: 27
Issue: 4
Pages: 742 - 756
DOI: 10.1093/hmg/ddx429
OADOI: https://oadoi.org/10.1093/hmg/ddx429
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Subjects:
Funding: 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; DevelopObese) [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 (NF-SI-0611–10196) [D.A.L]); Australian NHMRC Fellowships Scheme (619667) [G.W.M]. For study-specific funding, please see Supplementary Material. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Funding to pay the Open Access publication charges for this article was provided by the Charity Open Access Fund (COAF).
Copyright information: © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
  https://creativecommons.org/licenses/by/4.0/