Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10−6 in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10−9; odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10−9; OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI1.
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Avon Longitudinal Study of Parents and Children (ALSPAC): The authors are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The authors would also like to acknowledge 23andMe for our genotyping collaboration. The UK MRC (74882), the Wellcome Trust (076467) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors, and J.P.B. and S.F.A.G. will serve as guarantors for the content.
Northern Finnish Birth Cohort Studies 1966 (NFBC1966) and 1986 (NFBC1986): The authors thank P. Rantakallio (launch of NFBC1966 and NBC1986) and O. Tornwall and M. Jussila (DNA biobanking). The authors would like to acknowledge the contribution of the late Academian of Science Leena Peltonen. B.V. was supported by the Economic Social Research Council (ESRC; ES/H016058/1). J.B. is supported by a Wellcome Trust fellowship grant (WT088431MA). NFBC1966 and NFBC1986 received financial support from the Academy of Finland (104781, 120315, 129269, 1114194, the Center of Excellence in Complex Disease Genetics and SALVE), the University Hospital Oulu, the Biocenter Oulu, the University of Oulu (75617), the European Commission (EURO-BLCS; Framework 5 award; QLG1-CT-2000-01643), the US National Heart, Lung, and Blood Institute (NHLBI; 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01)), the US National Institutes of Health (NIH) and National Institute of Mental Health (NIMH; 5R01MH63706:02), the European Network for Genetic and Genomic Epidemiology (ENGAGE) project and grant agreement HEALTH-F4-2007-201413, the UK MRC (G0500539, G0600705 and PrevMetSyn/SALVE) and the Wellcome Trust (UK; GR069224). DNA extraction, sample quality control, biobank upkeep and aliquotting were performed at the National Public Health Institute at Biomedicum Helsinki (Finland) and were supported financially by the Academy of Finland and Biocentrum Helsinki.
British 1958 Birth Cohort (B58C): S. Ring, W. McArdle and J. Johnson are thanked for help with data linkage. E.H. holds the UK Department of Health Public Health Career Scientist Award. Analyses were funded by the British Heart Foundation (PG/09/023) and as part of the Public Health Research Consortium (supported by the UK Department of Health Policy Research Programme). C.M.L. is a Wellcome Trust Research Career Development Fellow (086596/Z/08/Z). R.M. was funded by grants from the European Commission Framework Programme 7 (FP7; 201413 and 245536), the Estonian government (SF0180142s08) and the European Union (EU) through the European Regional Development Fund (ERDF) and within the framework of the Centre of Excellence in Genomics and the University of Tartu (SP1GVARENG). The views expressed in this publication are those of the authors and not necessarily those of the UK Department of Health. Information about the wider program of the PHRC is available (see URLs). Collection of DNA in the 1958 Birth Cohort was funded by the UK MRC (G0000934) and the Wellcome Trust (068545/Z/02). This research used resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the US National Institute of Allergy and Infectious Diseases, the US National Human Genome Research Institute, the US National Institute of Child Health and Human Development and the Juvenile Diabetes Research Foundation International (JDRF) and supported by the NIDDK (U01 DK062418). This study makes use of data generated by the Wellcome Trust Case Control Consortium 2. A full list of investigators who contributed to generation of the data is available from the Wellcome Trust Case Control Consortium website. Funding for the project was provided by the Wellcome Trust (083948). Work was undertaken at Great Ormond Street Hospital and the Institute of Child Health at University College London, which received some funding from the UK Department of Health's NIHR (Biomedical Research Centres funding). The UK MRC provides funds for the MRC Centre of Epidemiology for Child Health.
French Young Study (FRENCH YOUNG): The authors thank the subjects and families who participated in this study. This work was supported by grants from the Agence Nationale de la Recherche, the Conseil Régional Nord-Pas de Calais as part of Fonds Européen de Développement Economique et Regional, Genome Quebec as part of Genome Canada and the UK MRC.
Lifestyle—Immune System—Allergy Study and German Infant Study on the Influence of Nutrition Intervention (LISA+GINI): The LISAplus study was funded by Helmholtz Zentrum München. The GINIplus study was funded by Helmholtz Zentrum München and by a grant from the German Federal Ministry for Education, Science, Research and Technology 292 (01 EE 9401-4). In addition, both studies were partly supported by the Competence Network Obesity, which receives funding from the German Federal Ministry of Education and Research (FKZ; 01GI0826) and the Munich Center of Health Sciences (MC Health) as part of the Ludwig-Maximilians University Munich (LMU) initiative.
Western Australian Pregnancy Cohort (RAINE) Study: The authors are grateful to the participants of the Raine Study and their families and to the Raine Study research staff for cohort coordination and data collection. The authors gratefully acknowledge the National Health and Medical Research Council of Australia for its long-term contribution to funding the study over the last 20 years and also acknowledge the following institutions for providing funding for the Core Management of the Raine Study: The University of Western Australia (UWA), the Raine Medical Research Foundation, the UWA Faculty of Medicine, Dentistry and Health Sciences, The Telethon Institute for Child Health Research, Curtin University and the Women and Infants Research Foundation. The authors gratefully acknowledge the assistance of the Western Australian DNA Bank (National Health and Medical Research Council of Australia National Enabling Facility). The authors also acknowledge the support of the National Health and Medical Research Council of Australia (403981 and 003209) and the Canadian Institutes of Health Research (MOP-82893).
Children's Hospital of Philadelphia (CHOP): The authors thank the network of primary care clinicians and the patients and families for their contribution to this project and to clinical research facilitated by the Pediatric Research Consortium (PeRC) at The Children's Hospital of Philadelphia. R. Chiavacci, E. Dabaghyan, H. Thomas, K. Harden, A. Hill, K. Fain, C. Johnson-Honesty, C. Drummond, S. Harrison, S. Wildrick, C. Kim, E. Frackelton, G. Otieno, K. Thomas, C. Hou, K. Thomas and M.L. Garris provided expert assistance with genotyping and/or data collection and management. The authors would also like to thank S. Kristinsson, L.A. Hermannsson and A.K. Raförninnehf for extensive software design and contributions. This research was financially supported by an Institute Development Award from the Children's Hospital of Philadelphia, a Research Development Award from the Cotswold Foundation and by a grant from the US NIH (R01 HD056465).
Essen Obesity Study (ESSEN): The authors thank all the participants of this study. This work was supported by grants from the German Federal Ministry of Education and Research (BMBF: 01KU0903 and NGFN-Plus: 01GS0820 and 01GS0830) and the Deutsche Forschungsgemeinschaft (DFG; HE 1446/4-1).
Helsinki Birth Cohort Study (HBCS): The Helsinki Birth Cohort Study (HBCS/HBCS 1934-44) thanks D. Barker, C. Osmond, E. Kajantie and T. Forsen. Major financial support was received from the Academy of Finland (209072 and 129255) and the British Heart Foundation. DNA extraction, sample quality control, biobank upkeep and aliquotting were performed at the National Institute for Health and Welfare (Helsinki, Finland).
Cardiovascular Risk in Young Finns Study (YF): The expert technical assistance in statistical analyses of I. Lisinen is gratefully acknowledged. The Young Finns Study has been financially supported by the Academy of Finland (126925, 121584, 124282, 129378 (SALVE), 117787 (Gendi) and 41071 (Skidi)), the Social Insurance Institution of Finland (Kuopio), Tampere and Turku University Hospital Medical Funds (9M048 for TeLeht), the Juho Vainio Foundation, the Paavo Nurmi Foundation, the Finnish Foundation of Cardiovascular Research, the Finnish Cultural Foundation, the Tampere Tuberculosis Foundation and the Emil Aaltonen Foundation.
Copenhagen Study on Asthma in Childhood (COPSAC): The authors thank all the families participating in the COPSAC cohort for their effort and commitment. The authors also thank the COPSAC study team. COPSAC is funded by private and public research funds, all of which are listed on the COPSAC website (see URLs). The Lundbeck Foundation, the Pharmacy Foundation of 1991, the Augustinus Foundation, the Danish MRC and The Danish Pediatric Asthma Centre provided core support for COPSAC. The funding agencies did not have any role in study design, data collection and analysis, the decision to publish or preparation of the manuscript.
Control Male–Genetics of Overweight Young Adults (CM-GOYA) study: This study was conducted as part of the activities of the Danish Obesity Research Centre (DanORC; see URLs) and the MRC Centre for Causal Analyses in Translational Epidemiology (UK MRC Causal Analyses in Translational Epidemiology (CAITE)).
Generation R Study (GENERATIONR): The authors gratefully acknowledge the contributions of the children and their parents, the general practitioners, the hospitals and the midwives and pharmacies in Rotterdam. The authors would like to thank K. Estrada, T.A. Knoch, A. Abuseiris, L.V. de Zeeuw and R. de Graaf for their help in creating GRIMP and BigGRID, MediGRID and Services@MediGRID/D-Grid (funded by the German Bundesministerium fuer Forschung und Technology; 01-AK-803-A-H and 01-IG-07015-G) for access to their grid computing resources. The authors thank M. Jhamai, M. Ganesh, P. Arp, M. Verkerk, L. Herrera and M. Peters for their help in creating, managing and performing quality control for the GWAS database. Also, the authors thank K. Estrada and C. Medina-Gomez for their support in the creation and analysis of imputed data. The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and the Faculty of Social Sciences of Erasmus University Rotterdam, the Municipal Health Service, Rotterdam area, the Rotterdam Homecare Foundation and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC; Rotterdam). The generation and management of GWAS genotype data for the Generation R Study were performed at the Genetic Laboratory of the Department of Internal Medicine at Erasmus Medical Center. The Generation R Study is made possible by financial support from the Erasmus Medical Center (Rotterdam), the Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development (ZonMw; 21000074). V.J. received grants from the Netherlands Organization for Health Research and Development (90700303 and 916.10159). Additional support was provided to H.R.T. by a grant from the Dutch Kidney Foundation (C08.2251).
Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) Study: The HELENA Study received funding from the EU Sixth Research and Technological Development (RTD) Framework Program (FOOD-CT-2005-007034). This work was also supported by the Conseil Régional du Nord-Pas de Calais and by the ERDF in the framework of the Contrat de Projet Etat-Région (CPER) Cardio-diabète (09220016).
Young Hearts Project: The Young Hearts Project has received support from the British Heart Foundation (PG/1996183/9569), the Wellcome Trust (052515/2/97/2) and the Department of Health and Social Services in Northern Ireland.
German Infant Study on the influence of Nutrition Intervention (GINI): GINI Munich: The study team wishes to acknowledge Helmholtz Zentrum München, the German Research Center for Environmental Health, the Institute of Epidemiology, Munich (J. Heinrich, H.E. Wichmann, S. Sausenthaler, C.-M. Chen, E. Thiering, C. Tiesler, M. Standl, M. Schnappinger and P. Rzehak), the Department of Pediatrics at Marien Hospital, Wesel (D. Berdel, A. von Berg, C. Beckmann and I. Groß), the Department of Pediatrics at Ludwig-Maximilians University, Munich (S. Koletzko, D. Reinhard and S. Krauss-Etschmann), the Department of Pediatrics at the Technical University, Munich (C.P. Bauer, I. Brockow, A. Grübl and U. Hoffmann), the Institut für Umweltmedizinische Forschung (IUF) at Heinrich-Heine-University, Düsseldorf (U. Krämer, E. Link and C. Cramer) and the Centre for Allergy and Environment at the Technical University, Munich (H. Behrendt).
Children's Health Study (CHS): The authors are indebted to the school principals, teachers, students and parents in each of the 12 study communities for their cooperation and especially thank the members of the health testing field team for their efforts. This work was supported by the Southern California Environmental Health Sciences Center (5P30ES007048) funded by the US National Institute of Environmental Health Sciences (NIEHS), the Children's Environmental Health Center (5P01ES009581, R826708-01 and RD831861-01) funded by the US NIEHS and the Environmental Protection Agency, the US NIEHS (5P01ES011627, 5R01ES014447, 5R01ES014708, 5R01ES016535 and 5R03ES014046), the US NHLBI (5R01HL061768, 5R01HL076647, 5R01HL087680, 1RC2HL101543 and 1RC2HL101651), the Environmental Protection Agency (R831845) and the Hastings Foundation.
Severe Childhood Onset Obesity Project United Kingdom (SCOOP-UK): The authors acknowledge the support of the Wellcome Trust (077016/Z/05/Z), the UK MRC and the NIHR Cambridge Biomedical Research Centre.
INfancia y Medio Ambiente (Environment and Childhood) Project (INMA): The authors are grateful to S. Fochs, A. Sànchez, M. López, N. Pey, M. Ferrer, A. Quiles, S. Pérez, G. León, E. Romero, M. Andreu, N. Galiana, M.D. Climent and A. Cases for their assistance in contacting the families and administering the questionnaires. The authors would particularly like to thank all the participants for their generous collaboration. A full roster of investigators at the INMA Project can be found at the project's website (see URLs). This study was funded by grants from the Instituto de Salud Carlos III (CB06/02/0041, G03/176, FIS PI041436, PI081151, PI041705, PS09/00432, FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314 and 09/02647), the Spanish Ministry of Science and Innovation (SAF2008-00357), the European Commission (the ENGAGE Project and HEALTH-F4-2007-201413), the Fundació La Marató de TV3, the Generalitat de Catalunya (CIRIT 1999SGR 00241), the Conselleria de Sanitat Generalitat Valenciana and the Fundación Roger Torné. Part of the DNA extraction and genotyping was performed at the Spanish National Genotyping Centre (CEGEN-Barcelona).
Project Viva (VIVA): The authors thank the staff and participants of Project Viva and S. Rifas-Shiman for expert statistical programming. This work was supported by a grant from the US NIH (R01 DK075787).
Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study: The PIAMA birth cohort study is a collaboration of the Institute for Risk Assessment Sciences at University Utrecht (B. Brunekreef), the Centre for Prevention and Health Services Research, the National Institute for Public Health and the Environment, Bilthoven (A.H. Wijga and H.A. Smit), The Department of Pediatrics in the Division of Respiratory Medicine at Erasmus Medical Center–Sophia's Children Hospital, Rotterdam (J.C. de Jongste), the Departments of Epidemiology (M. Kerkhof), Pulmonology (D.S. Postma) and Pediatric Pulmonology and Pediatric Allergology (G.H. Koppelman) of the GRIAC Research Institute, the University Medical Center Groningen and the University of Groningen and the Department of Immunopathology at Sanquin Research, Amsterdam (R.C. Aalberse). The study team gratefully acknowledges the participants in the PIAMA birth cohort study and all coworkers who helped in conducting the medical examinations, field work and data management. The PIAMA study was funded by grants from the Dutch Asthma Foundation (3.4.01.26, 3.2.06.022, 3.4.09.081 and 3.2.10.085CO), the ZON-MW Netherlands Organization for Health Research and Development (912-03-031), the Stichting Astmabestrijding, the Ministry of the Environment and ZON-MW Biobanking and Biomolecular Research Infrastructure (BBMRI)-NL.
Supplementary Note, Supplementary Tables 1–10 and Supplementary Figures 1 and 2
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International Journal of Obesity (2019)