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New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism

Abstract

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

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Figure 1: Regional plots of seven loci associated with birth weight at P < 5 × 10−8.
Figure 2: Associations between birth weight and loci previously associated with adult traits.

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Acknowledgements

A complete list of acknowledgments is given in the Supplementary Note. Major funding for the research in this paper is provided by the Academy of Finland (project grants 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), 41071 (Skidi), 209072, 129255, 104781, 120315, 129269, 1114194, 206374, 251360, 139900/24300796, Center of Excellence in Complex Disease Genetics and SALVE) and Biocentrum Helsinki; Arthritis Research UK; the Augustinus Foundation; the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL); the Biomedical Research Council, Singapore (BMRC 06/1/21/19/466); BIF: Boehringer Ingelheim Fonds (travel grant to A.T.); the British Heart Foundation; the C.G. Sundell Foundation; the Canadian Institutes of Health Research (grant MOP-82893); Cancer Research UK; the Chief Scientist Office of the Scottish Government; the Children's Hospital of Philadelphia (Institute Development Award); Conselleria de Sanitat Generalitat Valenciana; the Copenhagen Graduate School of Health Sciences; the Cotswold Foundation (Research Development Award); the Curtin University and Women and Infants Research Foundation; the Danish Health Insurance Societies (Health Fund); the Danish Medical Research Council; the Danish National Research Foundation; the Danish Pediatric Asthma Centre; the Danish Pharmacists' Fund; the Danish Strategic Research Council; the Darlington Trust; the Department of Health and Social Services in Northern Ireland; Deutsche Forschungsgemeinschaft (DFG); Diabetes Hilfs- und Forschungsfonds Deutschland (DHFD; travel grant to M. Stumvoll); Diabetes UK (grants RD08/0003704 and RD08/0003692); the Dunhill Medical Trust; the Dutch Asthma Foundation (grants 3.4.01.26, 3.2.06.022, 3.4.09.081 and 3.2.10.085CO); the Dutch Ministry of the Environment (EFRE): Europäische Fonds für Regionale Entwicklung (LIFE Child Obesity); the Egmont Foundation; the Else Kröner-Fresenius Foundation; the Emil Aaltonen Foundation (T.L.); the ENGAGE project and grant agreement HEALTH-F4-2007-201413; the Erasmus Medical Center; Erasmus University, Rotterdam; the European Commission (EURO-BLCS, Beta-JUDO, Framework 5 award QLG1-CT-2000-01643, GABRIEL (Integrated Program LSH-2004-1.2.5-1 contract 018996), framework programme 6 EUROSPAN project (contract LSHG-CT-2006-018947), Sixth Research, Technological Development (RTD) Framework Programme (Contract FOOD-CT-2005-007034) and Seventh Framework Programme (FP7/2007-2013)); the European Research Council (ERC Advanced; 230374); the European Science Foundation (ESF; EU/QLRT-2001-01254); the Exeter NHS Research and Development; Faculty of Biology and Medicine of Lausanne; the Finnish Foundation of Cardiovascular Research; the Finnish Cultural Foundation; the Finnish Innovation Fund Sitra; the Finnish Ministry of Education and Culture; the Finnish Ministry of Social Affairs and Health; the Finnish Social Insurance Institution; the Foundation for Paediatric Research; Fundació La Marató de TV3; Fundación Roger Torné; Generalitat de Catalunya–Interminesterial Council for Research and Technological Innovation (CIRIT; 1999SGR) 00241; the German Diabetes Association (A.T.); the German Bundesministerium fuer Forschung und Technology (grants 01 AK 803 A-H and 01 IG 07015 G); the German Research Foundation for the Clinical Research Group Atherobesity KFO 152 (KO3512/1 to A.K.); GlaxoSmithKline; the Hagedorn Research Institute; Instituto de Salud Carlos III (CB06/02/0041, FIS PI041436, PI081151, PI041705 and PS09/00432 and FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314 and 09/02647); the Interdisciplinary Centre for Clinical Research at the University of Leipzig (B27 to A.T. and M. Stumvoll); the Integrated Research and Treatment Centre (IFB) Adiposity Diseases; the Jackstädt-Foundation; the Juho Vainio Foundation; the Juvenile Diabetes Research Foundation International (JDRF); Kuopio, Tampere and Turku University Hospital Medical Funds (grant 5031343 to T.A. Lakka and grant 9M048 to T.L.); The Lundbeck Foundation; the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care (LuCAMP); the March of Dimes Birth Defects Foundation (6-FY09-507); the MRC, UK (grants 74882, G0000934, G0601653, G0500539, G0600705, G0601261, G0600331, PrevMetSyn/SALVE PS0476 and MC-A760-5QX00); the Munich Center of Health Sciences (MC Health); the National Health and Medical Research Council of Australia (grants 403981 and 003209); the US National Human Genome Research Institute; the US National Institute of Allergy and Infectious Diseases; the US National Institute of Child Health and Human Development; the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); the US National Institutes of Health (grants U01DK062418, U01HG004423, U01HG004446, U01HG004438, R01DK075787, 1R01HD056465-01A, R01D0042157-01A, DK078150, TW05596, HL085144, HD054501, RR20649, ES10126, DK56350 and Biomedical Research Centers funding); the Netherlands Bioinformatics Centre (NBIC) BioAssist (RK/2008.024); a National Heart, Lung, and Blood Institute (NHLBI) grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01); the NIH Genetic Association Information Network (GAIN); the NIH/National Institute of Mental Health (NIMH) (5R01MH63706:02 and MH081802); the Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06); the Novo Nordisk Foundation Center for Basic Metabolic Research; the Center for Medical Systems Biology (CMSB; NWO Genomics); the Netherlands Organization for Scientific Research (NWO: Social Sciences (MaGW) and the Netherlands Organization for Health Research and Development (ZonMw) (Middelgroot-911-09-032, Spinozapremie 56-464-14192, 904-61-090, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 985-10-002, 40-0056-98-9032 and 912-03-031); the Paavo Nurmi Foundation; the Peninsula NIHR Clinical Research Facility; the Pharmacy Foundation of 1991; the PhD School of Molecular Metabolism University of Southern Denmark; the Raine Medical Research Foundation; the Royal Society; the Sigrid Juselius Foundation; South West NHS Research and Development; the Spanish Ministry of Science and Innovation (SAF2008-00357), Turku University Hospital; the Swiss National Science Foundation (33CSCO-122661); the Tampere Tuberculosis Foundation; the Telethon Institute for Child Health Research; the Turku University Foundation; the US Centers for Disease Control and Prevention; University Hospital Oulu, Biocenter, the University of Oulu (75617); the University of Bristol; the University of Potsdam; the University of Southampton; the University of Western Australia (UWA); the VU Institute for Health and Care Research (EMGO+) and the Neuroscience Campus Amsterdam (NCA); the Wellcome Trust (grants GR069224, WT088806, 068545/Z/02, 076467, 085301, 090532, 083270, 083948, 085541/Z/08/Z, WT089549 and WT083431MA); and the Yrjö Jahnsson Foundation.

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Contributions

Discussion group (decided on analyses specific to the project): J.P.B., T.M.F., R.M.F. (co-lead/chair), S.F.A.G., M.H., V.W.V.J., M.-R.J., M.I.M., D.O.M.-K., C.E.P., I.P. (co-lead), N.J.T. and H.Y. Writing group (drafted and edited manuscript): T.M.F., R.M.F. (co-lead/chair), B.J.H., M.H. (co-lead), V.W.V.J., M.-R.J., M.I.M., D.O.M.-K., I.P., H.R.T., N.J.T. and H.Y. (co-lead). Meta-analyses and other key analyses: Stage 1, discovery meta-analysis: R.M.F. (lead), J. Heikkinen (data exchange), D.O.M.-K., I.P. and U.S. Stage 2, follow-up and overall meta-analysis: R.M.F., M.H. (co-lead), I.P. and H.Y. (co-lead). Sensitivity meta-analyses: R.M.F. and H.Y. (lead). Analyses of known type 2 diabetes, blood pressure and height loci (including ALSPAC mother-child pair analyses): R.M.F. (lead), D.A.L., N.J.T. and H.Y. Postnatal data analysis: D.L.C., R.M.F., M. Kaakinen, D.O.M.-K. (lead), E.T. and U.S. Trans-ancestry analyses and genotype risk score analysis: M.H. (lead), I.P. (chair), N.J.T., H.Y., (CHOP) J.P.B., H.H. and S.F.A.G., (CLHNS) Y.W. and K.L.M., (Generation R) H.R.T. and V.W.V.J., (MRC Keneba) B.J.H., A.J.F. and A.M.P., (SAUDI) D.O.M.-K., F.S.A. and B.F.M. and (SCORM) L.-K.G. and S.-M.S. Cohort -specific contributions: Project design: (B58C) E.H. and C.P.; (ALSPAC) D.A.L., G.D.S. and N.J.T.; (BBC) B.H. and M.I.M.; (CHOP) J.P.B., S.F.A.G., H.H. and J.Z.; (CLHNS) L.S.A. and K.L.M.; (COLAUS) P.V.; (COPSAC-2000) H.B.; (COPSAC-REGISTRY) H.B. and K.B.; (DNBC) M.M.; (EFSOCH) T.M.F. and A.T.H.; (EPIC and EPIC-Norfolk) K.K.O.; (Generation R) A.H., V.W.V.J. and D.O.M.-K.; (HBCS) J.G.E.; (HCS) C.C.; (HELENA) F. Gottrand and L.A.M.; (INMA) X.E.; (Leipzig-Kids) A.K. and W.K.; (LISAplus and GINIplus) J. Heinrich; (MRC Keneba) A.J.F., B.J.H. and A.M.P.; (NFBC1966 and NFBC1986) M.-R.J. and U.S.; (NTR) D.I.B.; (ORCADES) J.F.W.; (PANIC) T.A.L.; (PIAMA) M. Kerkhof, G.H.K. and D.S.P.; (RAINE) J.P.N. and C.E.P.; (SAUDI) F.S.A. and B.F.M.; (SCORM) L.-K.G. and S.-M.S.; (SORBS) M. Stumvoll and A.T.; (STRIP) H.N., O.T.R. and O.S.; (SWS) K.M.G. and H.M.I.; (TEENAGE) G.V.D. and I.N.; (YF) T.L. and J.S.V.; and (Young Hearts Project) C.A.G.B. Sample collection and phenotyping: (B58C) D.J.B., E.H. and C.P.; (ALSPAC) D.A.L. and G.D.S.; (BBC) B.H., T.P. and T.S.; (CHOP) H.H.; (CLHNS) L.S.A. and C.W.K.; (COLAUS) P.V.; (COPSAC-2000) H.B., L.P. and N.H.V.; (COPSAC-REGISTRY) H.B., K.B., M.V.H., D.M.H. and E.K.-M.; (DNBC) B.F., F. Geller and M.M.; (EFSOCH) A.T.H., B.A.K. and B.M.S.; (EPIC and EPIC-Norfolk) K.K.O.; (ERF) B.A.O. and C.M.v.D.; (Generation R) A.H., V.W.V.J., D.O.M.-K. and H.R.T.; (GoDARTS) E.R.P.; (HBCS) J.G.E.; (HELENA) F. Gottrand and L.A.M.; (INMA) M.G.; (Inter99) T.H., T.J., O.P., A.V. and D.R.W.; (Leipzig-Kids) A.K. and W.K.; (LISAplus and GINIplus) C.F.; (MRC Keneba) A.J.F.; (NFBC1966 and NFBC1986) M.-R.J., M. Kaakinen and A.P.; (NTR) D.I.B., E.J.C.d.G., J.M.V. and G.W.; (ORCADES) J.F.W.; (PANIC) T.O.K., T.A.L. and V. Lindi; (PIAMA) M. Kerkhof, G.H.K. and D.S.P.; (Project Viva) M.W.G.; (RAINE) J.P.N. and C.E.P.; (SAUDI) A.A.-O., B.F.M. and D.M.M.; (SCORM) L.-K.G. and S.-M.S.; (SORBS) M. Stumvoll and A.T.; (STRIP) H.N., O.T.R. and O.S.; (SWS) K.M.G.; (TEENAGE) C.K.-G. and I.N.; (YF) T.L. and J.S.V.; and (Young Hearts Project) C.A.G.B. Genotyping: (B58C and B58C-Replication) A.J.B., C.J.G., M.I.M. and N.R.R.; (ALSPAC) J.P.K., G.M. and S.M.R.; (BBC) A.J.B., B.H., M.I.M., T.P., N.R.R. and T.S.; (CHOP) S.F.A.G. and H.H.; (COPSAC-REGISTRY) M.V.H. and D.M.H.; (EFSOCH) T.M.F. and R.M.F.; (EPIC and EPIC-Norfolk) R.J.F.L., N.J.W. and K.K.O.; (ERF) B.A.O. and C.M.v.D.; (Generation R) F.R. and A.G.U.; (GoDARTS) K.Z.; (HBCS) E.W.; (HCS) J.W.H.; (HELENA) J.D. and A. Meirhaeghe; (INMA) M.B.; (Inter99) E.A.A., T.H. and M.N.H.; (Leipzig-Kids) A.K.; (LISAplus and GINIplus) N.K. and C.M.T.T.; (MRC Keneba) B.J.H.; (NFBC1966 and NFBC1986) A.I.F.B., J.L.B., P.F. and M.I.M.; (NTR) J.-J.H.; (ORCADES) J.F.W.; (PANIC) T.A.L. and V. Lindi; (PIAMA) M. Kerkhof, G.H.K. and D.S.P.; (Project Viva) J.N.H. and R.M.S.; (RAINE) J.P.N. and C.E.P.; (SAUDI) B.F.M. and D.M.M.; (SCORM) S.-M.S.; (SORBS) M. Stumvoll; (STRIP) O.T.R.; (SWS) J.W.H.; (TEENAGE) A.J.B., C.J.G., M.I.M. and N.R.R.; (YF) T.L.; and (Young Hearts Project) P.A. and A. Meirhaeghe. Statistical analysis: (B58C) D.J.B.; (B58C-Replication) M.H.; (ALSPAC) D.M.E., B.S.P. and N.J.T.; (BBC) B.H., M.H., T.P. and T.S.; (CHOP) J.P.B., S.F.A.G. and H.Z.; (CLHNS) Y.W.; (COLAUS) Z.K.; (COPSAC-2000) E.K.-M.; (COPSAC-REGISTRY) E.K.-M.; (DNBC) B.F. and F. Geller; (EFSOCH) R.M.F. and H.Y.; (EPIC and EPIC-Norfolk) M.d.H. and J.H.Z.; (ERF) A.I. and E.M.v.L.; (Generation R) D.O.M.-K. and H.R.T.; (GoDARTS) E.R.P. and K.Z.; (HBCS) D.L.C.; (HCS) K.A.J.; (HELENA) A. Meirhaeghe; (INMA) M.B.; (Inter99) E.A.A. and M.N.H.; (Leipzig-Kids) A. Mahajan; (LISAplus and GINIplus) E.T.; (MRC Keneba) A.J.F. and B.J.H.; (NFBC1966 and NFBC1986) P.C., S.D., M.H., M. Kaakinen, I.P., S.S. and U.S.; (NTR) J.-J.H.; (ORCADES) M. Kirin; (PANIC) V. Lindi; (PIAMA) M. Kerkhof; (Project Viva) M.W.G., J.N.H. and R.M.S.; (RAINE) N.M.W.; (SAUDI) D.O.M.-K.; (SCORM) L.-K.G. and S.-M.S.; (SORBS) V. Lagou and I.P.; (STRIP) O.T.R. and M. Saarinen; (SWS) S.J.B. and H.M.I.; (TEENAGE) I.N. and M.H.; (YF) D.L.C. and E.W.; and (Young Hearts Project) P.A. and A. Meirhaeghe.

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Correspondence to Mark I McCarthy or Struan F A Grant or Vincent W V Jaddoe or Marjo-Riitta Jarvelin or Nicholas J Timpson or Inga Prokopenko or Rachel M Freathy.

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Horikoshi, M., Yaghootkar, H., Mook-Kanamori, D. et al. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism. Nat Genet 45, 76–82 (2013). https://doi.org/10.1038/ng.2477

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