Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Robert A. Scott, Vasiliki Lagou, Ryan P. Welch, Eleanor Wheeler, May E. Montasser, Jian'An Luan, Reedik MäGi, Rona J. Strawbridge, Emil Rehnberg, Stefan Gustafsson, Stavroula Kanoni, Laura J. Rasmussen-Torvik, Loïc Yengo, Cecile Lecoeur, Dmitry Shungin, Serena Sanna, Carlo Sidore, Paul C D Johnson, J. Wouter Jukema, Toby JohnsonAnubha Mahajan, Niek Verweij, Gudmar Thorleifsson, Jouke Jan Hottenga, Sonia Shah, Albert V. Smith, Bengt Sennblad, Christian Gieger, Perttu Salo, Markus Perola, Nicholas J. Timpson, David M. Evans, Beate St Pourcain, Ying Wu, Jeanette S. Andrews, Jennie Hui, Lawrence F. Bielak, Wei Zhao, Momoko Horikoshi, Pau Navarro, Aaron Isaacs, Jeffrey R. O'Connell, Kathleen Stirrups, Veronique Vitart, Caroline Hayward, Tõnu Esko, Evelin Mihailov, Ross M. Fraser, Tove Fall, Benjamin F. Voight, Soumya Raychaudhuri, Han Chen, Cecilia M. Lindgren, Andrew P. Morris, Nigel W. Rayner, Neil Robertson, Denis Rybin, Ching Ti Liu, Jacques S. Beckmann, Sara M. Willems, Peter S. Chines, Anne U. Jackson, Hyun Min Kang, Heather M. Stringham, Kijoung Song, Toshiko Tanaka, John F. Peden, Anuj Goel, Andrew A. Hicks, Ping An, Martina MüLler-Nurasyid, Anders Franco-Cereceda, Lasse Folkersen, Letizia Marullo, Hanneke Jansen, Albertine J. Oldehinkel, Marcel Bruinenberg, James S. Pankow, Kari E. North, Nita G. Forouhi, Ruth J F Loos, Sarah Edkins, Tibor V. Varga, Göran Hallmans, Heikki Oksa, Mulas Antonella, Ramaiah Nagaraja, Stella Trompet, Ian Ford, Stephan J L Bakker, Augustine Kong, Meena Kumari, Bruna Gigante, Christian Herder, Patricia B. Munroe, Mark Caulfield, Jula Antti, Massimo Mangino, Kerrin Small, Iva Miljkovic, Yongmei Liu, Mustafa Atalay, Wieland Kiess, Alan L. James, Fernando Rivadeneira, Andre G. Uitterlinden, Colin N A Palmer, Alex S F Doney, Gonneke Willemsen, Johannes H. Smit, Susan Campbell, Ozren Polasek, Lori L. Bonnycastle, Serge Hercberg, Maria Dimitriou, Jennifer L. Bolton, Gerard R. Fowkes, Peter Kovacs, Jaana LindströM, Tatijana Zemunik, Stefania Bandinelli, Sarah H. Wild, Hanneke V. Basart, Wolfgang Rathmann, Harald Grallert, Winfried Maerz, Marcus E. Kleber, Bernhard O. Boehm, Annette Peters, Peter P. Pramstaller, Michael A. Province, Ingrid B. Borecki, Nicholas D. Hastie, Igor Rudan, Harry Campbell, Hugh Watkins, Martin Farrall, Michael Stumvoll, Luigi Ferrucci, Dawn M. Waterworth, Richard N. Bergman, Francis S. Collins, Jaakko Tuomilehto, Richard M. Watanabe, Eco J C De Geus, Brenda W. Penninx, Albert Hofman, Ben A. Oostra, Bruce M. Psaty, Peter Vollenweider, James F. Wilson, Alan F. Wright, G. Kees Hovingh, Andres Metspalu, Matti Uusitupa, Patrik K E Magnusson, Kirsten O. Kyvik, Jaakko Kaprio, Jackie F. Price, George V. Dedoussis, Panos Deloukas, Pierre Meneton, Lars Lind, Michael Boehnke, Alan R. Shuldiner, Cornelia M. Van Duijn, Andrew D. Morris, Anke Toenjes, Patricia A. Peyser, John P. Beilby, Antje KöRner, Johanna Kuusisto, Markku Laakso, Stefan R. Bornstein, Peter E H Schwarz, Timo A. Lakka, Rainer Rauramaa, Linda S. Adair, George Davey Smith, Tim D. Spector, Thomas Illig, Ulf De Faire, Anders Hamsten, Vilmundur Gudnason, Mika Kivimaki, Aroon Hingorani, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Dorret I. Boomsma, Kari Stefansson, Pim Van Der Harst, Josée Dupuis, Nancy L. Pedersen, Naveed Sattar, Tamara B. Harris, Francesco Cucca, Samuli Ripatti, Veikko Salomaa, Karen L. Mohlke, Beverley Balkau, Philippe Froguel, Anneli Pouta, Marjo Riitta Jarvelin, Nicholas J. Wareham, Nabila Bouatia-Naji, Mark I. McCarthy, Paul W. Franks, James B. Meigs, Tanya M. Teslovich, Jose C. Florez, Claudia Langenberg, Erik Ingelsson, Inga Prokopenko, Iněs Barroso

Research output: Contribution to journalArticlepeer-review

516 Scopus citations

Abstract

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

Original languageEnglish (US)
Pages (from-to)991-1005
Number of pages15
JournalNature Genetics
Volume44
Issue number9
DOIs
StatePublished - Sep 2012

Bibliographical note

Funding Information:
AGES: The AGESReykjavik study was supported by a contract from the National Institutes of Health (N01AG12100), National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament).

Funding Information:
ALSPAC: We 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 UK Medical Research Council (grant 74882), the Wellcome Trust (grants 076467 and 092731) and the University of Bristol provide core support for ALSPAC.

Funding Information:
Amish: We gratefully thank our Amish community and research volunteers for their longstanding partnership in research and acknowledge the dedication of our Amish liaisons, field workers and the Amish Research Clinic staff, without whom these studies would not have been possible. The Amish studies are supported by grants and contracts from the US NIH, including R01 AG18728, R01 HL088119, U01 GM074518, U01 HL07251506, U01 HL84756, R01 DK54261, the University of Maryland General Clinical Research Center grant M01 RR 16500, the MidAtlantic Nutrition Obesity Research Center grant P30 DK72488, the Baltimore Diabetes Research and Training Center grant P60DK79637 and the T32 training grant AG000219 (M.E.M.). In addition, this project was supported by National Research Initiative Competitive Grant 20073520517883 from the US Department of Agriculture (USDA) National Institute of Food and Agriculture.

Funding Information:
ARIC: We thank the staff and participants of the ARIC study for their important contributions. The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study that is supported by National Heart, Lung, and Blood Institute (NHLBI) contracts N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and US NIH contract HHSN268200625226C. Infrastructure was partly supported by grant UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. We are grateful for resources provided by the University of Minnesota Supercomputing Institute.

Funding Information:
ASAP: The ASAP study was funded by a donation from F. Lundberg.

Funding Information:
ASCOT: We thank all ASCOT trial participants, physicians, nurses and practices in the participating countries for their important contributions to the study. In particular, we thank C. Muckian and D. Toomey for their help in DNA extraction, storage and handling. This work was supported by Pfizer for the ASCOT study and the collection of the ASCOT DNA repository, by Servier Research Group and by Leo Laboratories. Genotyping was funded by a Wellcome Trust Strategic Award (083948).

Funding Information:
BLSA: The BLSA was supported in part by the Intramural Research Program of the National Institute on Aging of the US NIH. A portion of that support was through an R&D contract with the MedStar Research Institute.

Funding Information:
Busselton Health Study (BSN): The Busselton Health Study acknowledges the generous support for the 1994/5 followup study from Healthway, Western Australia, the numerous Busselton community volunteers who assisted with data collection and the study participants from the Shire of Busselton. The BHS is supported by The Great Wine Estates of the Margaret River region of Western Australia.

Funding Information:
CHS: This research at CHS was supported by NHLBI contracts N01HC85239, N01HC85079 through N01HC85086, N01HC35129, N01 HC15103, N01 HC55222, N01HC75150 and N01HC45133 and NHLBI grants HL080295, HL075366, HL087652 and HL105756, with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629, AG15928, AG20098 and AG027058 from the National Institute on Aging (see URLs). DNA handling and genotyping were supported in part by National Center for Research Resources grant M01RR00425 to the CedarsSinai General Clinical Research Center Genotyping Core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. B. Psaty serves on a Data and Safety Monitoring Board (DSMB) for a clinical trial of a device funded by the manufacturer (ZollLifecor).

Funding Information:
CLHNS: We thank the Office of Population Studies Foundation research and data collection teams and the study participants who generously provided their time for this study. This work was supported by US NIH grants DK078150, TW05596, HL085144, RR20649, ES10126 and DK56350.

Funding Information:
CoLaus: The authors also express their gratitude to the participants in the Lausanne CoLaus study and to the investigators who have contributed to the recruitment, in particular, Y. Barreau, A.L. Bastian, B. Ramic, M. Moranville, M. Baumer, M. Sagette, J. Ecoffey and S. Mermoud for data collection. The CoLaus study was supported by research grants from the Swiss National Science Foundation (grant 33CSCO122661), from GlaxoSmithKline and from the Faculty of Biology and Medicine of Lausanne, Switzerland. P.V. and G.W. received an unrestricted grant from GlaxoSmithKline to build the CoLaus study.

Funding Information:
CROATIA-Korcula: The authors collectively thank a large number of individuals for their help in organizing, planning and carrying out the field work related to the project: S. Jankovic and staff at the University of Split Medical School; B. Salzer from the biochemistry laboratory ‘Salzer’; local general practitioners and nurses; and the employees of several other Croatian institutions who participated in the field work, including but not limited to the University of Rijeka; the Croatian Institute of Public Health; and the Institutes of Public Health in Split and Dubrovnik. SNP genotyping of the Korcula samples was carried out by Helmholtz Zentrum München. The work is supported by the European Union framework program 6 EUROSPAN project (contract LSHGCT2006018947) and grant ~21610803150302 (to I.R.) from the Croatian Ministry of Science, Education and Sport. Studies carried out on the Croatian island of Korcula were supported by Medical Research Council, UK.

Funding Information:
CROATIA-Split: The authors collectively thank a large number of individuals for their help in organizing, planning and carrying out the field work related to the project: S. Jankovic and staff at the University of Split Medical School; B. Salzer from the biochemistry laboratory ‘Salzer’; local general practitioners and nurses; and the employees of several other Croatian institutions who participated in the field work. including but not limited to the University of Rijeka; the Croatian Institute of Public Health; and the Institutes of Public Health in Split and Dubrovnik. SNP genotyping of the Split samples was carried out by AROS Applied Biotechnology. The work is supported by grant ~21610803150302 (to I.R.) from the Croatian Ministry of Science, Education and Sport. Studies carried out in the Croatian city of Split were supported by Medical Research Council, UK.

Funding Information:
CROATIA-Vis: The authors collectively thank a large number of individuals for their help in organizing, planning and carrying out the field work related to the project: P. Rudan and staff of the Institute for Anthropological Research in Zagreb; S. Jankovic and staff at the University of Split Medical School; A. VorkoJovic and staff and medical students of the Andrija Stampar School of Public Health of the Faculty of Medicine at the University of Zagreb; B. Salzer from the biochemistry laboratory ‘Salzer’; local general practitioners and nurses; and the employees of several other Croatian institutions who participated in the field work. including but not limited to the University of Rijeka; the Croatian Institute of Public Health; and the Institutes of Public Health in Split and Dubrovnik. SNP genotyping of the Vis samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility at Western General Hospital. The work is supported by the European Union framework program 6 EUROSPAN project (contract LSHGCT2006018947) and grant ~21610803150302 (to I.R.) from the Croatian Ministry of Science, Education and Sport. Studies carried out on the Croatian island of Vis were supported by Medical Research Council, UK.

Funding Information:
DESIR: We thank all the participants of the D.E.S.I.R study, E. Eury and S. Lobbens for technical support for the genotyping and O. Lantieri and M. Marre from the D.E.S.I.R study. Genotyping was supported by the Conseil Régional NordPasdeCalais Fonds Européen de Développement Economique et Regional CPER axe Cartdiodiabète 2010–2011 grant to N.B.N.

Funding Information:
deCODE: We thank the individuals who participated in the study and whose contributions made this work possible. The research performed at deCODE genetics was in part funded through the European Union’s Seventh Framework Programme (FP7/20072013) ENGAGE project, grant HEALTHF42007201413.

Funding Information:
DIAGEN: We are grateful to all of the patients who cooperated in this study and to their referring physicians and diabetologists in Saxony. The presented study was supported by the Commission of the European Communities, Directorate C–Public Health and Risk Assessment, Health & Consumer Protection, grant agreement 2004310, and by the Dresden University of Technology Funding Grant Med Drive.

Funding Information:
DPS: The DPS has been financially supported by grants from the Academy of Finland (117844, 40758, 211497 and 118590), the EVO funding of the Kuopio University Hospital from the Ministry of Health and Social Affairs (5254), the Finnish Funding Agency for Technology and Innovation (40058/07), the Nordic Centre of Excellence on Systems biology in controlled dietary interventions and cohort studies (SYSDIET; 070014), the Finnish Diabetes Research Foundation, the Yrjö Jahnsson Foundation (56358), the Sigrid Juselius Foundation, the Juho Vainio Foundation and TEKES grants 70103/06 and 40058/07.

Funding Information:
DR’s EXTRA: The DR’s EXTRA Study was supported by grants from the Ministry of Education and Culture of Finland (627;20042011), the Academy of Finland (102318 and 123885), Kuopio University Hospital, the Finnish Diabetes Association, the Finnish Heart Association, the Päivikki and Sakari Sohlberg Foundation, a European Union FP6 Integrated Project (EXGENESIS, LSHMCT2004005272), the city of Kuopio and the Social Insurance Institution of Finland (4/26/2010).

Funding Information:
EAS (Metabochip): EAS was supported by the British Heart Foundation. Genotyping was supported by a grant from the Chief Scientist Office, Scotland, and was performed at the Wellcome Trust Clinical Research Facility in Edinburgh.

Funding Information:
EGCUT: EGCUT was financed by FP7 grants (201413 and 245536), a grant from the Estonian government (SF0180142s08), the European Union through the European Regional Development Fund, in the framework of the Centre of Excellence in Genomics and a grant from the University of Tartu (SP1GVARENG).

Funding Information:
Ely: We are grateful to all the volunteers and to the staff of St. Mary’s Street Surgery, Ely and the study team. The Ely Study was funded by the MRC (MC_U106179471) and Diabetes UK. Genotyping in the Ely and Fenland studies was supported in part by an MRCGlaxoSmithKline pilot programme grant (G0701863).

Funding Information:
ERF: We thank the participants from Genetic Research in Isolated Populations, Erasmus Rucphen Family and their general practitioners, who made this work possible. This study is financially supported by the Netherlands Organization for Scientific Research (NWO), the European Union framework program 6 EUROSPAN project (contract LSHGCT2006018947), the ENGAGE project (grant HEALTHF42007201413), the International Stichting Alzheimer Onderzoek (ISAO), Hersenstichning Nederland (HSN) and the Centre for Medical Systems Biology (CMSB 1&2) in the framework of the Netherlands Genomics Initiative (NGI).

Funding Information:
FamHS: The Family Heart Study (FamHS) was supported by US NIH grants RO1HL087700 and RO1HL088215 (to M.A.P.) from HNLBI and RO1DK8925601 and RO1DK075681 (to I.B.B.) from NIDDK.

Funding Information:
Fenland: The Fenland Study is funded by the Wellcome Trust and the Medical Research Council (MC_U106179471). We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for assistance with recruitment. We thank the Fenland Study Investigators, Fenland Study Coordination team and the Epidemiology Field, Data and Laboratory teams. Biochemical assays were performed by the National Institute for Health Research, Cambridge Biomedical Research Centre, Core Biochemistry Assay Laboratory, and the Cambridge University Hospitals NHS Foundation Trust, Department of Clinical Biochemistry.

Funding Information:
FIN-D2D 2007: The FIND2D study has been financially supported by the hospital districts of Pirkanmaa, South Ostrobothnia and Central Finland, the Finnish National Public Health Institute (current National Institute for Health and Welfare), the Finnish Diabetes Association, the Ministry of Social Affairs and Health in Finland, the Academy of Finland (grant 129293), the Commission of the European Communities, Directorate C–Public Health (grant agreement 2004310) and Finland’s Slottery Machine Association.

Funding Information:
FINRISK/DILGOM: The DILGOM study received support from the EteläPohjanmaa Hospital District, the PohjoisPohjanmaa Hospital District, the KeskiSuomi Hospital District, the Pirkanmaa Hospital District and the PohjoisSavo Hospital District. The DILGOM survey was funded by the Academy of Finland (grant 118065). V.S. was supported by the Academy of Finland (grant 139635 and 129494).

Funding Information:
Framingham Heart Study: This research was conducted in part using data and resources from the Framingham Heart Study of the NHLBI of the US NIH and the Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the NHLBI’s Framingham Heart Study (contract N01HC25195) and its contract with Affymetrix for genotyping services (contract N02HL64278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGAII) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The study is also supported by NIDDK R01 DK078616 to J.B.M., J.D. and J.C.F. and NIDDK K24 DK080140 to J.B.M.

Funding Information:
FUSION: Support for FUSION was provided by NIH grants R01DK062370 (to M. Boehnke), R01DK072193 (to K.L.M.) and intramural project number 1Z01HG000024 (to F.S.C.). Genomewide genotyping was conducted by the Johns Hopkins

Funding Information:
University Genetic Resources Core Facility SNP Center at the Center for Inherited Disease Research (CIDR), with support from CIDR NIH contract N01HG65403.

Funding Information:
GEMS: We thank the investigators S. Grundy, P. Barter, R. McPherson, R. Mahley, T. Bersot and A. Kesaniemi for collection of the samples. The GEMS study was sponsored in part by GlaxoSmithKline.

Funding Information:
GENOA: We thank E. Boerwinkle and J. Cunningham for their help with genotyping. The Genetic Epidemiology Network of Arteriopathy (GENOA) study is supported by US NIH grants HL087660 and HL100245 from the NHLBI.

Funding Information:
GenomEUtwin: We acknowledge support from the European Commission under Quality of Life and Management of the Living Resources of the Fifth Framework Program (GenomEUtwin QLG2CT200201254). The study is also supported by ENGAGE–European Network for Genetic and Genomic Epidemiology, FP7HEALTHF42007, grant agreement 201413.

Funding Information:
GLACIER: The GLACIER Study is nested within the Northern Sweden Health and Disease Study, and phenotyping was conducted as part of the Västerbotten Intervention Project. We thank the participants and the investigators from these studies for their valuable contributions, with specific thanks to L. Weinehall, Å. Agren, K. Enquist and T. Johansson. The GLACIER Study and part the salary of P.W.F. were funded by grants from the Swedish Research Council, the Swedish HeartLung Foundation, Novo Nordisk, the Umeå Medical Research Foundation and the Swedish Diabetes Association (to P.W.F.). Genotyping for this specific project was funded by the Wellcome Trust Sanger Institute. I.B. acknowledges funding from Wellcome Trust grant 098051, the UK NIHR Cambridge Biomedical Research Centre and the MRC Centre for Obesity and Related Metabolic Diseases. We thank E. Gray, D. Simpkin, S. Hunt and the staff of the Wellcome Trust Sanger Institute Sample Logistics, Genotyping and Variation Informatics Facilities.

Funding Information:
GoDARTS: The study was funded by the Wellcome Trust, Tenovus Tayside and the Medical Research Council, UK.

Funding Information:
Health ABC: This study was supported by National Institute on Aging contracts N01AG62101, N01AG62103 and N01AG62106 and in part by the Intramural Research Program of the US NIH, the National Institute on Aging. The GWAS was funded by National Institute on Aging grant 1R01AG03209801A1 to Wake Forest University Health Sciences, and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to Johns Hopkins University, contract HHSN268200782096C.

Funding Information:
Health2000: The Health 2000 Study is funded by the National Institute for Health and Welfare (THL), the Finnish Centre for Pensions (ETK), the Social Insurance Institution of Finland (KELA), the Local Government Pensions Institution (KEVA) and other organizations listed on the website of the survey. GWAS genotyping was supported by the Wellcome Trust Sanger Institute.

Funding Information:
InChianti: The InCHIANTI study baseline (1998–2000) was supported as a targeted project (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (contracts 263 MD 9164 and 263 MD 821336).

Funding Information:
KORA F4: We thank all members of field staff who were involved in the planning and conduct of the MONICA/KORA Augsburg studies. The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum München–Research Center for Environment and Health and supported by grants from the German Federal Ministry of Education and Research (BMBF), the Federal Ministry of Health, the Ministry of Innovation, Science, Research and Technology of North RhineWestphalia, the German National Genome Research Network (NGFN) and the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ.

Funding Information:
LEIPZIG_ADULT_IFB: We thank all those who participated in the studies. This work was supported by grants from Integrated Research and Treatment Centre (IFB) Adiposity Diseases (K736 to A. Körner) and from the Clinical Research Group Atherobesity KFO 152 (projects BL 833/11 and Stu192/61).

Funding Information:
LEIPZIG_CHILHOOD_IFB: We are grateful to all the patients and families for contributing to the study. We greatly appreciate the support of the Obesity Team and the Auxo Team of the Leipzig University Children’s Hospital for management of the patients and to the Pediatric Research Center Lab Team for support with DNA banking. This work was supported by grants from Integrated Research and Treatment Centre (IFB) Adiposity Diseases (K736 to A. Körner) and from the Clinical Research Group Atherobesity KFO 152 (projects KO3512/12 to A.K.).

Funding Information:
LURIC: The authors extend appreciation to the participants in the LURIC study; without their collaboration, this article would not have been written. We thank the LURIC study team members who are either temporarily or permanently involved in patient recruitment, sample collection and data handling and the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg and Ulm. LURIC received funding through the Sixth Framework Programme (integrated project Bloodomics, grant LSHMCT2004503485) and Seventh Framework Programme (integrated project AtheroRemo, grant agreement 201668) of the European Union.

Funding Information:
METSIM: The METSIM study was funded by the Academy of Finland (grants 77299 and 124243).

Funding Information:
MICROS: For the MICROS study, we thank the primary care practitioners R. Stocker, S. Waldner, T. Pizzecco, J. Plangger and U. Marcadent and the personnel of the Hospital of Silandro (Department of Laboratory Medicine) for their participation and collaboration in the research project. In South Tyrol, the study was supported by the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano and the South Tyrolean Sparkasse Foundation.

Funding Information:
NFBC66: We thank P. Rantakallio (launch of NFBC1966 and 1986) and O. Tornwall and M. Jussila (DNA biobanking). The authors would like to acknowledge the contribution of the late Academian of Science Leena Peltonen. NFBC1986(1966) received financial support from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission (EUROBLCS, Framework 5 award QLG1CT200001643), NHLBI grant 5R01HL08767902 through the STAMPEED program (1RL1MH08326801), US NIH/National Institute of Mental Health (NIMH) (5R01MH63706:02), ENGAGE project and grant agreement HEALTHF42007201413, the Medical Research Council, UK (G0500539, G0600705 and PrevMetSyn/SALVE) and the Wellcome Trust (project grant GR069224). DNA extraction, sample quality control, biobank upkeeping and aliquotting were performed at the National Public Health Institute at Biomedicum Helsinki and were supported financially by the Academy of Finland and Biocentrum Helsinki.

Funding Information:
NFBC86: The research of V.L. is funded in part through the European Community’s Seventh Framework Programme (FP7/20072013), ENGAGE project, grant agreement HEALTHF42007201413. The research of I.P. is funded in part through the European Community’s Seventh Framework Programme (FP7/20072013), ENGAGE project, grant agreement HEALTHF42007201413.

Funding Information:
NTRNESDA: Funding was obtained from the Netherlands Organization for Scientific Research (NWO; MagW/ZonMW, 90461090, 98510002, 90461193, 48004004, 40005717, Addiction31160008 and Middelgroot-91109032); Spinozapremie (SPI 5646414192); the Center for Medical Systems Biology (CMSB) (NWO Genomics); NBIC/BioAssist/RK/2008.024; Biobanking and Biomolecular Resources Research Infrastructure (BBMRINL; 184.021.007); the VU University Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); the European Science Foundation (ESF): Genomewide Analyses of European Twin and Population Cohorts (EU/QLRT-200101254); the European Community’s Seventh Framework Program (FP7/2007-2013): ENGAGE (HEALTHF42007201413); the European Science Council (ERC) Genetics of Mental Illness (230374); Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH06845706); Collaborative Study of the Genetics of DZ Twinning (US NIH R01D004215701A); and the Genetic Association Information Network, a publicprivate partnership between the NIH and Pfizer, Affymetrix and Abbott Laboratories.

Funding Information:
ORCADES: We would like to acknowledge the invaluable contributions of L. Anderson, the research nurses in Orkney and the administrative team in Edinburgh. ORCADES was supported by the Scottish Executive Health Department, the Royal Society and the European Union Framework Programme 6 EUROSPAN project (contract LSHGCT2006018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh.

Funding Information:
PIVUS: Genotyping was performed by the SNP&SEQ Technology Platform in Uppsala (see URLs). We thank T. Axelsson, A.C. Wiman and C. Pöntinen for their excellent assistance with genotyping. The SNP Technology Platform is supported by Uppsala University, Uppsala University Hospital and the Swedish Research Council for Infrastructures. E.I. is supported by grants from the Swedish Research Council, the Swedish HeartLung Foundation, the Swedish Foundation for Strategic Research and the Royal Swedish Academy of Science.

Funding Information:
PREVEND: PREVEND genetics is supported by the Dutch Kidney Foundation (grant E033), the US National Institutes of Health (grant LM010098), The Netherlands Organization for Health Research and Development (NWO VENI grant 916.761.70) and the Dutch Interuniversity Cardiology Institute Netherlands (ICIN).

Funding Information:
PROCARDIS: The PROCARDIS study was supported by the European Community Sixth Framework Programme (LSHMCT-2007037273), AstraZeneca, the British Heart Foundation, the Oxford BHF Centre of Research Excellence, the Wellcome Trust (075491/Z/04), the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish HeartLung Foundation, the Torsten and Ragnar Söderberg Foundation, the Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council (560283).

Funding Information:
PROSPER: The PROSPER/PHASE study has received funding from the European Union’s Seventh Framework Programme (FP7/20072013) under grant agreement HEALTHF22009223004. PROSPER/PHASE is supported by grants from the Interuniversity Cardiology Institute of the Netherlands (ICIN) and the Durrer Center for Cardiogenetic Research, both of which are Institutes of the Netherlands Royal Academy of Arts and Sciences (KNAW); the Center for Medical Systems Biology (CMSB), a center of excellence approved by the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO); and the Netherlands Consortium for Healthy Ageing (NCHA). The research leading to the PROSPER study was sponsored by Bristol Myers Squibb.

Funding Information:
Rotterdam Study: The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We thank P. Arp, M. Jhamai, M. Verkerk, L. Herrera and M. Peters for their help in creating the GWAS database and K. Estrada and M.V. Struchalin for their support in the creation and analysis of imputed data. The generation and management of GWAS genotype data for the Rotterdam Study are supported by the Netherlands Organization of Scientific Research NWO Investments (175.010.2005.011 and 91103012). This study is funded by the Research Institute for Diseases in the Elderly (01493015; RIDE2), Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) project 050060810, the European Community’s Seventh Framework Programme (FP7/20072013) and the ENGAGE project, grant agreement HEALTHF42007201413. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam.

Funding Information:
SardiNIA: The authors thank all the volunteers and the mayors of the four towns involved. This work was supported in part by the Intramural Research Program of the National Institute on Aging through the US NIH and by contract NO1AG1-2109 from the NIA to the SardiNIA (ProgeNIA) team.

Funding Information:
SCARFSHEEP: Funding for the study was provided by the European Commission (LSHMCT2007037273), the Swedish HeartLung Foundation, the Swedish Research Council (2669, 8691), the Knut and Alice Wallenberg Foundation, the Foundation for Strategic Research, the Torsten and Ragnar Söderberg Foundation, the Strategic Cardiovascular Programme of Karolinska Institutet and the Stockholm County Council (560183).

Funding Information:
SORBS: We thank all those who participated in the studies. This work was supported by grants from Integrated Research and Treatment Centre (IFB) Adiposity Diseases (K736 to M.S. and A. Körner), from the Clinical Research Group Atherobesity KFO 152 (projects BL 833/11 to M.B. and Stu192/61 to M.S.). R.M. acknowledges financial support from the European Commission under a Marie Curie IntraEuropean Fellowship. P.K. acknowledges financial support from the Boehringer Ingelheim Foundation.

Funding Information:
SUVIMAX : This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Institut National de la Recherche Agronomique, the Université Paris 13, the Centre National de Génotypage and the Commissariat à L’Energie Atomique.

Funding Information:
Swedish Twin Registry: We thank T. Axelsson, A.C. Wiman and C. Pöntinen for their excellent assistance with genotyping. This work was supported by grants from the US NIH (AG028555, AG08724, AG04563, AG10175 and AG08861), the Swedish Research Council, the Swedish HeartLung Foundation, the Swedish Foundation for Strategic Research, the Royal Swedish Academy of Science and ENGAGE (within the European Union Seventh Framework Programme, HEALTHF42007201413). Genotyping was performed by the SNP&SEQ Technology Platform (see URLs). The SNP Technology Platform is supported by Uppsala University, Uppsala University Hospital and the Swedish Research Council for Infrastructures.

Funding Information:
THISEAS: We thank all the dieticians and clinicians for their contribution to the project. Recruitment for THISEAS was partially funded by a research grant (PENED 2003) from the Greek General Secretary of Research and Technology.

Funding Information:
TRAILS: TRAILS (TRacking Adolescents’ Individual Lives Survey) is a collaborative project involving various departments of the University Medical Center and University of Groningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen and the Parnassia Bavo group, all in The Netherlands. We are grateful to all adolescents and their parents and teachers who participated in this research and to everyone who worked on this project and made it possible. TRAILS has been financially supported by grants from the Netherlands Organization for Scientific Research NWO (Medical Research Council program grant GBMW 94038011; ZonMW Brainpower grant 100001004; ZonMw Risk Behavior and Dependence grants 606060098018 and 606060097118; ZonMw Culture and Health grant 26198710; Social Sciences Council mediumsized investment grants GBMaGW 48001006 and GBMaGW 48007001; Social Sciences Council project grants GBMaGW 45703018, GBMaGW 45204314 and GBMaGW 45206004; NWO largesized investment grant 175.010.2003.005; and NWO Longitudinal Survey and Panel Funding 48108013); the Sophia Foundation for Medical Research (projects 301 and 393), the Dutch Ministry of Justice (WODC), the European Science Foundation (EuroSTRESS project FP006) and the participating universities. Statistical analyses were carried out on the Genetic Cluster Computer (see URLs), which is financially supported by the Netherlands Scientific Organization (NWO 48005003) along with a supplement from the Dutch Brain Foundation.

Funding Information:
TwinsUK: The study was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/20072013), grant agreement HEALTHF22008201865GEFOS, (FP7/20072013), ENGAGE project grant agreement HEALTHF42007201413, and the Fifth Framework Programme GenomEUtwin Project (QLG2CT200201254). The study also receives support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St. Thomas’ National Health Service (NHS) Foundation Trust in partnership with King’’s College London. T.D.S. is an NIHR senior Investigator. The project also received support from a Biotechnology and Biological Sciences Research Council (BBSRC) project grant (G20234). The authors acknowledge the funding and support of the National Eye Institute via an NIH/CIDR genotyping project (to T. Young).

Funding Information:
ULSAM: Genotyping was performed by the SNP&SEQ Technology Platform in Uppsala (see URLs). We thank T. Axelsson, A.C. Wiman and C. Pöntinen for their excellent assistance with genotyping. The SNP Technology Platform is supported by Uppsala University, Uppsala University Hospital and the Swedish Research Council for Infrastructures. E.I. is supported by grants from the Swedish Research Council, the Swedish HeartLung Foundation, the Swedish Foundation for Strategic Research, and the Royal Swedish Academy of Science.

Funding Information:
Whitehall II: The WHII study has been supported by grants from the Medical Research Council; the Economic and Social Research Council; British Heart Foundation (BHF); the Health and Safety Executive; the Department of Health; the NHLBI (HL36310), the US, NIH: National Institute on Aging (AG13196), US, NIH; the Agency for Health Care Policy Research (HS06516); and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health. Genotyping in WHII was supported by BHF grant PG/07/133/24260 and by an MRCGlaxoSmithKline pilot programme grant (85374). S. Raychaudhuri is supported by the US NIH (K08AR055688).

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