Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

Iryna O. Fedko; Maria Groen-Blokhuis; Jouke-Jan Hottenga; Catharina E. M. Van Beijsterveldt; Tanja G. M. Vrijkotte; Dorret I. Boomsma; Early Growth Genetics (EGG) Consortium

doi:10.1371/journal.pgen.1008718

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

Iryna O. Fedko, Maria Groen-Blokhuis, Jouke-Jan Hottenga, Catharina E. M. Van Beijsterveldt, Tanja G. M. Vrijkotte, Dorret I. Boomsma, Early Growth Genetics (EGG) Consortium

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R _g ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

Original language	English
Article number	e1008718
Pages (from-to)	1-26
Number of pages	26
Journal	PLoS Genetics
Volume	16
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1008718
Publication status	Published - 12 Oct 2020

Funding

CP received funding from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. MMcC is a Wellcome Senior Investigator and an NIHR Senior Investigator. MMcC received funding from Wellcome (090532, 106130, 098381, 203141, 212259), NIDDK (U01-DK105535), and NIHR (NF-SI-0617-10090). TGMV was supported by ZonMW (TOP 40–00812–98–11010). DLC was supported by the American Diabetes Association Grant 1-17-PDF-077. SFAG is supported by the Daniel B. Burke Chair for Diabetes Research and NIH Grant R01 HD058886. NVT is funded by a pre-doctoral grant from the Agència de Gestió d’Ajuts Universitaris i de Recerca (2017 FI_B 00636), Generalitat de Catalunya – Fons Social Europeu. BK received personal funding from the European Research Council Advanced Grant META-GROWTH (ERC-2012-AdG – no. 322605). BF was supported by an Oak Foundation Fellowship. RMF and RNB are supported by Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). ATH is supported by a Wellcome Trust Senior Investigator award (grant number 098395/Z/12/Z). DM is supported by a Canada Research Chair. DLC was supported by the American Diabetes Association Grant 1-17-PDF-077. JTL was supported by the Finnish Cultural Foundation. DIB received a KNAW Academy Professor Award (PAH/6635). MH received PhD scholarship funding from TARGET (http://target.ku. dk), The Danish Diabetes Academy (http:// danishdiabetesacademy.dk) and the Copenhagen Graduate School of Health and Medical Sciences. VWVJ received funding from the Netherlands Organization for Health Research and Development (VIDI 016.136.361) and the European Research Council (ERC-2014-CoG-648916). ISF was supported by the European Research Council, Wellcome Trust (098497/Z/12/Z), Medical Research Council (MRC_MC_UU_12012/5), the NIHR Cambridge Biomedical Research Centre, the Botnar Foundation, the Bernard Wolfe Health Neuroscience Endowment and the European Community’s Seventh Framework Programme (FP7/2007-2013) project Beta-JUDO no279153. IB acknowledges funding from Wellcome (WT206194). ES works in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3). GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1). KC received funds from the French National Agency of Research, F-CRIN/FORCE. All funding for the studies that provided the underlying data for this manuscript can be found in S1 Text. The funders had no role in study design, data collection and analysis, data interpretation, decision to publish, or preparation of the manuscript. Funding:CPreceivedfundingfromtheNational InstituteforHealthResearchBiomedicalResearch CentreatGreatOrmondStreetHospitalfor ChildrenNHSFoundationTrustandUniversity CollegeLondon.MMcCisaWellcomeSenior InvestigatorandanNIHRSeniorInvestigator. MMcCreceivedfundingfromWellcome(090532, 106130,098381,203141,212259),NIDDK(U01-DK105535),andNIHR(NF-SI-0617-10090).TGMV wassupportedbyZonMW(TOP40–00812–98– 11010).DLCwassupportedbytheAmerican DiabetesAssociationGrant1-17-PDF-077.SFAGis supportedbytheDanielB.BurkeChairforDiabetes ResearchandNIHGrantR01HD058886.NVTis fundedbyapre-doctoralgrantfromtheAgènciade Gestio ´d’AjutsUniversitarisideRecerca(2017 FI_B00636),GeneralitatdeCatalunya–Fons SocialEuropeu.BKreceivedpersonalfundingfrom theEuropeanResearchCouncilAdvancedGrant META-GROWTH(ERC-2012-AdG–no.322605). BFwassupportedbyanOakFoundation Fellowship.RMFandRNBaresupportedbySir HenryDaleFellowship(WellcomeTrustandRoyal Societygrant:WT104150).ATHissupportedbya WellcomeTrustSeniorInvestigatoraward(grant number098395/Z/12/Z).DMissupportedbya CanadaResearchChair.DLCwassupportedbythe AmericanDiabetesAssociationGrant1-17-PDF-077.JTLwassupportedbytheFinnishCultural Foundation.DIBreceivedaKNAWAcademy ProfessorAward(PAH/6635).MHreceivedPhD scholarshipfundingfromTARGET(http://target.ku.

Funders	Funder number
Bernard Wolfe Health Neuroscience Endowment
Copenhagen Graduate School of Health and Medical Sciences
ERC-2012-AdG	AmericanDiabetesAssociationGrant1-17-PDF-077, number098395/Z/12/Z, WT104150
GeneralitatdeCatalunya
META-GROWTH
TARGET
National Institutes of Health
American Diabetes Association	1-17-PDF-077
National Institute of Diabetes and Digestive and Kidney Diseases	NF-SI-0617-10090, U01-DK105535
National Institute of Child Health and Human Development	R01HD058886
Oak Foundation
Wellcome Trust
Seventh Framework Programme	WT206194, FP7/2007-2013, 322605
NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
Danish Diabetes Academy
Medical Research Council	MC_UU_00011/3, MC_UU_00011/1, MRC_MC_UU_12012/5
National Institute for Health and Care Research	203141, 098381, 106130, 090532, 212259
Royal Society	098395/Z/12/Z
University College London
European Research Council
University of Bristol
Agence Nationale de la Recherche
Canada Research Chairs
ZonMw	ERC-2014-CoG-648916, TOP 40–00812–98–11010, 098497/Z/12/Z, VIDI 016.136.361
Generalitat de Catalunya
Agència de Gestió d'Ajuts Universitaris i de Recerca	2017 FI_B00636
Suomen Kulttuurirahasto	PAH/6635
Great Ormond Street Hospital for Children
Fondation Botnar
NIHR Cambridge Biomedical Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pgen.1008718

https://dx.plos.org/10.1371/journal.pgen.1008718

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Cite this

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title = "Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits",

abstract = "The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R g ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood. ",

author = "Suzanne Vogelezang and Bradfield, {Jonathan P.} and Ahluwalia, {Tarunveer S.} and Curtin, {John A.} and Lakka, {Timo A.} and Niels Grarup and Markus Scholz and {Van Der Most}, {Peter J.} and Claire Monnereau and Evie Stergiakouli and Anni Heiskala and Momoko Horikoshi and Fedko, {Iryna O.} and Natalia Vilor-tejedor and Cousminer, {Diana L.} and Marie Standl and Wang, {Carol A.} and Jorma Viikari and Frank Geller and Carmen {\'I}{\~n}iguez and Niina Pitk{\"a}nen and Alessandra Chesi and Jonas Bacelis and Loic Yengo and Maties Torrent and Ioanna Ntalla and {\O}yvind Helgeland and Saskia Selzam and Vonk, {Judith M.} and Zafarmand, {Mohammed H.} and Barbara Heude and Farooqi, {Ismaa Sadaf} and Akram Alyass and Beaumont, {Robin N.} and Have, {Christian T.} and Peter Rzehak and Bilbao, {Jose Ramon} and Schnurr, {Theresia M.} and In{\^e}s Barroso and Klaus B{\o}nnelykke and Beilin, {Lawrence J.} and Lisbeth Carstensen and Marie-aline Charles and Bo Chawes and Karine Cl{\'e}ment and Ricardo Closa-monasterolo and Adnan Custovic and Eriksson, {Johan G.} and Joaquin Escribano and Maria Groen-Blokhuis and Veit Grote and Dariusz Gruszfeld and Hakon Hakonarson and Torben Hansen and Hattersley, {Andrew T.} and Mette Hollensted and Jouke-Jan Hottenga and Elina Hypp{\"o}nen and Stefan Johansson and Raimo Joro and Mika K{\"a}h{\"o}nen and Ville Karhunen and Wieland Kiess and Knight, {Bridget A.} and Berthold Koletzko and Andreas K{\"u}hnapfel and Kathrin Landgraf and Jean-paul Langhendries and Terho Lehtim{\"a}ki and Leinonen, {Jaakko T.} and Aihuali Li and Virpi Lindi and Estelle Lowry and Mariona Bustamante and Carolina Medina-gomez and Mads Melbye and Michaelsen, {Kim F.} and Morgen, {Camilla S.} and Mori, {Trevor A.} and Nielsen, {Tenna R. H.} and Harri Niinikoski and Oldehinkel, {Albertine J.} and Katja Pahkala and Kalliope Panoutsopoulou and Oluf Pedersen and Pennell, {Craig E.} and Christine Power and Reijneveld, {Sijmen A.} and Fernando Rivadeneira and Angela Simpson and Sly, {Peter D.} and Jakob Stokholm and Teo, {Kook K.} and Elisabeth Thiering and Timpson, {Nicholas J.} and Uitterlinden, {Andr{\'e} G.} and {Van Beijsterveldt}, {Catharina E. M.} and {Van Schaik}, {Barbera D. C.} and Marc Vaudel and Elvira Verduci and Vinding, {Rebecca K.} and Mandy Vogel and Eleftheria Zeggini and Sylvain Sebert and Lind, {Mads V.} and Brown, {Christopher D.} and Loreto Santa-marina and Eva Reischl and Christine Frithioff-b{\o}js{\o}e and David Meyre and Eleanor Wheeler and Ken Ong and Nohr, {Ellen A.} and Vrijkotte, {Tanja G. M.} and Koppelman, {Gerard H.} and Robert Plomin and Nj{\o}lstad, {P{\aa}l R.} and Dedoussis, {George D.} and Philippe Froguel and S{\o}rensen, {Thorkild I. A.} and Bo Jacobsson and Freathy, {Rachel M.} and Zemel, {Babette S.} and Olli Raitakari and Martine Vrijheid and Bjarke Feenstra and Leo-pekka Lyytik{\"a}inen and Harold Snieder and Holger Kirsten and Holt, {Patrick G.} and Joachim Heinrich and Elisabeth Wid{\'e}n and Jordi Sunyer and Boomsma, {Dorret I.} and Marjo-riitta J{\"a}rvelin and Antje K{\"o}rner and {Davey Smith}, George and Jens-christian Holm and Mustafa Atalay and Clare Murray and Hans Bisgaard and Mccarthy, {Mark I.} and Jaddoe, {Vincent W. V.} and Grant, {Struan F. A.} and Felix, {Janine F.} and Copenhaver, {Gregory P.} and {Early Growth Genetics (EGG) Consortium}",

year = "2020",

month = oct,

day = "12",

doi = "10.1371/journal.pgen.1008718",

language = "English",

volume = "16",

pages = "1--26",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "10",

}

TY - JOUR

T1 - Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

AU - Vogelezang, Suzanne

AU - Bradfield, Jonathan P.

AU - Ahluwalia, Tarunveer S.

AU - Curtin, John A.

AU - Lakka, Timo A.

AU - Grarup, Niels

AU - Scholz, Markus

AU - Van Der Most, Peter J.

AU - Monnereau, Claire

AU - Stergiakouli, Evie

AU - Heiskala, Anni

AU - Horikoshi, Momoko

AU - Fedko, Iryna O.

AU - Vilor-tejedor, Natalia

AU - Cousminer, Diana L.

AU - Standl, Marie

AU - Wang, Carol A.

AU - Viikari, Jorma

AU - Geller, Frank

AU - Íñiguez, Carmen

AU - Pitkänen, Niina

AU - Chesi, Alessandra

AU - Bacelis, Jonas

AU - Yengo, Loic

AU - Torrent, Maties

AU - Ntalla, Ioanna

AU - Helgeland, Øyvind

AU - Selzam, Saskia

AU - Vonk, Judith M.

AU - Zafarmand, Mohammed H.

AU - Heude, Barbara

AU - Farooqi, Ismaa Sadaf

AU - Alyass, Akram

AU - Beaumont, Robin N.

AU - Have, Christian T.

AU - Rzehak, Peter

AU - Bilbao, Jose Ramon

AU - Schnurr, Theresia M.

AU - Barroso, Inês

AU - Bønnelykke, Klaus

AU - Beilin, Lawrence J.

AU - Carstensen, Lisbeth

AU - Charles, Marie-aline

AU - Chawes, Bo

AU - Clément, Karine

AU - Closa-monasterolo, Ricardo

AU - Custovic, Adnan

AU - Eriksson, Johan G.

AU - Escribano, Joaquin

AU - Groen-Blokhuis, Maria

AU - Grote, Veit

AU - Gruszfeld, Dariusz

AU - Hakonarson, Hakon

AU - Hansen, Torben

AU - Hattersley, Andrew T.

AU - Hollensted, Mette

AU - Hottenga, Jouke-Jan

AU - Hyppönen, Elina

AU - Johansson, Stefan

AU - Joro, Raimo

AU - Kähönen, Mika

AU - Karhunen, Ville

AU - Kiess, Wieland

AU - Knight, Bridget A.

AU - Koletzko, Berthold

AU - Kühnapfel, Andreas

AU - Landgraf, Kathrin

AU - Langhendries, Jean-paul

AU - Lehtimäki, Terho

AU - Leinonen, Jaakko T.

AU - Li, Aihuali

AU - Lindi, Virpi

AU - Lowry, Estelle

AU - Bustamante, Mariona

AU - Medina-gomez, Carolina

AU - Melbye, Mads

AU - Michaelsen, Kim F.

AU - Morgen, Camilla S.

AU - Mori, Trevor A.

AU - Nielsen, Tenna R. H.

AU - Niinikoski, Harri

AU - Oldehinkel, Albertine J.

AU - Pahkala, Katja

AU - Panoutsopoulou, Kalliope

AU - Pedersen, Oluf

AU - Pennell, Craig E.

AU - Power, Christine

AU - Reijneveld, Sijmen A.

AU - Rivadeneira, Fernando

AU - Simpson, Angela

AU - Sly, Peter D.

AU - Stokholm, Jakob

AU - Teo, Kook K.

AU - Thiering, Elisabeth

AU - Timpson, Nicholas J.

AU - Uitterlinden, André G.

AU - Van Beijsterveldt, Catharina E. M.

AU - Van Schaik, Barbera D. C.

AU - Vaudel, Marc

AU - Verduci, Elvira

AU - Vinding, Rebecca K.

AU - Vogel, Mandy

AU - Zeggini, Eleftheria

AU - Sebert, Sylvain

AU - Lind, Mads V.

AU - Brown, Christopher D.

AU - Santa-marina, Loreto

AU - Reischl, Eva

AU - Frithioff-bøjsøe, Christine

AU - Meyre, David

AU - Wheeler, Eleanor

AU - Ong, Ken

AU - Nohr, Ellen A.

AU - Vrijkotte, Tanja G. M.

AU - Koppelman, Gerard H.

AU - Plomin, Robert

AU - Njølstad, Pål R.

AU - Dedoussis, George D.

AU - Froguel, Philippe

AU - Sørensen, Thorkild I. A.

AU - Jacobsson, Bo

AU - Freathy, Rachel M.

AU - Zemel, Babette S.

AU - Raitakari, Olli

AU - Vrijheid, Martine

AU - Feenstra, Bjarke

AU - Lyytikäinen, Leo-pekka

AU - Snieder, Harold

AU - Kirsten, Holger

AU - Holt, Patrick G.

AU - Heinrich, Joachim

AU - Widén, Elisabeth

AU - Sunyer, Jordi

AU - Boomsma, Dorret I.

AU - Järvelin, Marjo-riitta

AU - Körner, Antje

AU - Davey Smith, George

AU - Holm, Jens-christian

AU - Atalay, Mustafa

AU - Murray, Clare

AU - Bisgaard, Hans

AU - Mccarthy, Mark I.

AU - Jaddoe, Vincent W. V.

AU - Grant, Struan F. A.

AU - Felix, Janine F.

AU - Early Growth Genetics (EGG) Consortium

A2 - Copenhaver, Gregory P.

PY - 2020/10/12

Y1 - 2020/10/12

N2 - The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R g ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

AB - The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R g ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

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UR - http://www.scopus.com/inward/citedby.url?scp=85092931223&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1008718

DO - 10.1371/journal.pgen.1008718

M3 - Article

SN - 1553-7390

VL - 16

SP - 1

EP - 26

JO - PLoS Genetics

JF - PLoS Genetics

IS - 10

M1 - e1008718

ER -

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

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