The authors thank M. Boehnke (University of Michigan, Ann Arbor, Michigan, USA) for valuable comments on the manuscript. The authors wish to thank staff at Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark: A. Forman, T. Lorentzen, B. Andreasen and G. J. Klavsen for technical assistance and A. L. Nielsen, G. Lademann and M. M. H. Kristensen for management assistance.
Funding
This project was funded by the Lundbeck Foundation and produced by The Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp,
www.lucamp.org). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (
www.metabol.ku.dk). Further funding came from the Danish Council for Independent Research (Medical Sciences).
The Inter99 was initiated by Torben Jørgensen (PI), Knut Borch-Johnsen (co-PI), Hans Ibsen and Troels F. Thomsen. The steering committee comprises the former two and Charlotta Pisinger. The study was financially supported by research grants from the Danish Research Council, the Danish Centre for Health Technology Assessment, Novo Nordisk Inc., Research Foundation of Copenhagen County, Ministry of Internal Affairs and Health, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation, the Becket Foundation, and the Danish Diabetes Association.
The Health2006 was initiated by Allan Linneberg (PI) and Torben Jørgensen (co-PI). The study was financially supported by grants from the Velux Foundation, The Danish Medical Research Council, Danish Agency for Science, Technology and Innovation, The Aase and Ejner Danielsens Foundation, ALK-Abelló, (Hørsholm, Denmark) and Research Centre for Prevention and Health (the Capital Region of Denmark).
In Finland this work has been supported by the following grants to M. Laakso: Academy of Finland, the Finnish Diabetes Research Foundation, the Finnish Cardiovascular Research Foundation, and EVO grant from the Kuopio University Hospital (5263).
In the UK the Collection of the UK type 2 diabetes cases was supported by Diabetes UK, BDA Research and the UK Medical Research Council (Biomedical Collections Strategic Grant G0000649). The UK Type 2 Diabetes Genetics Consortium collection was supported by the Wellcome Trust (Biomedical Collections Grant GR072960). We acknowledge use of DNA from The UK Blood Services collection of Common Controls (UKBS-CC collection), funded by the Wellcome Trust grant 076113/C/04/Z and by NIHR programme grant to NHSBT (RP-PG-0310-1002). The collection was established as part of the Wellcome Trust Case Control Consortium (WTCCC). For the 1958 Birth Cohort, venous blood collection was funded by the Medical Research Council grant G0000934 (awarded under the Health of the Public initiative), peripheral blood lymphocyte preparation by Juvenile Diabetes Research Foundation/Wellcome Trust and the cell-line production, DNA extraction and processing by the Wellcome Trust grant 06854/Z/02/Z. The genotyping was supported by the Wellcome Trust (083270) and EU (ENGAGE: HEALTH-F4-2007- 201413). A. P. Morris is a Wellcome Trust Senior Fellow (081682/Z/06/Z) and M. McCarthy receives funding from the Oxford NIHR Biomedical Research Centre. We acknowledge the contribution of M. Sampson.
In the Netherlands the work in this study was financially supported by the Dutch Diabetes Research Foundation grant 2006.00.060 and Biobanking and Biomolecular Research Infrastructure the Netherlands (BBMRI-NL).
The D.E.S.I.R. cohort was supported by co-operative contracts between Inserm, CNAMTS, Novartis, Lilly and sanofi-aventis, by Inserm (Réseaux en Santé Publique, Interactions entre les determinants de la santé, Cohortes Santé TGIR 2008), by the Association Diabète Risque Vasculaire, the Fédération Française de Cardiologie, La Fondation de France, ALFEDIAM, ONIVINS, Société Francophone du Diabète; Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Lilly, Merck Santé, Novo Nordisk, Pierre Fabre, Roche, sanofi-aventis, Topcon.
Work in Sweden was supported by grants from the Swedish Research Foundation (Dnr-349-2006-6589, 2009-1039, 521-2010-3490) and Knut & Alice Wallenberg Foundation.
Work in Finland was supported by grants from the Sigrid Juselius Foundation, Folkhälsan Research Foundation and the Finnish Medical Society.
The Gene-Lifestyle interactions And Complex traits Involved in Elevated Disease Risk (GLACIER) study is nested within the Northern Swedish Health and Disease Study cohort and the Västerbotten Intervention Programme (VIP). The research programme was approved by the Ethical Review Board in Umeå, Sweden. We are indebted to the study participants who dedicated their time and samples to these studies. We also thank the VIP and Umeå Medical Biobank staff for biomedical data collection and preparation. We specifically thank Å. Ågren (Umeå Medical Biobank) for data organisation, and K. Enqvist and T. Johansson (Västerbottens County Council) for expert technical assistance with DNA preparation. The GLACIER Study was funded by project grants from Novo Nordisk (P. W. Franks [PWF]), the Swedish Heart-Lung Foundation (PWF), the Swedish Diabetes Association (to PWF), Påhlssons Foundation (PWF), the Swedish Research Council (PWF), Umeå University Career Development Award (PWF) and The Heart Foundation of Northern Sweden (PWF).
Author contributions
All authors substantially contributed to conception and design, acquisition of data, or analysis and interpretation of data used in the study.
OP, A. Albrechtsen, NG, YL, TS, JH, TH, JW and RN conceived, coordinated and executed the present study.
NG, TS, JH, M. Lajer, AAN, PR, LT, CC, IB, TL, DRW, AL, T. Jørgensen, TH and OP recruited and phenotyped study participants enrolled in exome sequencing (stage 1) and large-scale follow-up genotyping (stage 2).
SC, GC, JMD, ASFD, MD, TF, TMF, GH, ATH, GAH, JK, OL, M. Marre, ADM., GN, PN, CNAP, FR, OR, TT, EV, TVV, MW, LY, PWF, BB, PF, MIM, M. Laakso and LG recruited and phenotyped study participants used in replication study (stage 3).
A. Albrechtsen, YL, TS, GT, T. Jiang, SYK, TK, RW, HJ, HZ, XJ, HL, XL, TM, XM, BM, MT, BW, HW, FX, CY, XZ, JZ, QZ, HZ, YZ, JW, RN and OP performed exome sequencing and the related data analysis.
A. Albrechtsen, NG, TS, GT, HC, Q. Li, CN, LS, KB, YC, YG, KH, SH, XJ, JMJ, WL, Q. Liao, XL, MPM, YW, HW, XZ, QZ, WZ, HZ, JW, RN and OP performed stage 2 genotyping and statistical analyses.
A. Albrechtsen, NG, TS, APM, CL, SC, A. Stančáková, AJB, CJG, GH, NWR, FR, NR, OR, PES, MS, NVL, TVV, LMT, PWF, PF, M. Laakso and OP performed stage 3 genotyping and statistical analyses and meta-analyses.
JM, RRM, TWS, and MAV performed biological studies.
The overall analysis group consisted of A. Albrechtsen, NG, TS, SYK, TK, Q. Li, LS, YC, YG, QL and RN.
A. Albrechtsen, NG, TS, TH and OP wrote the initial manuscript and all authors contributed substantially to data interpretation and paper review and approved the final manuscript.
OP, GA, A. Astrup, LB, KK, TWS, TL, DRW, AL, T. Jørgensen, TH, JW and RN are founders of the Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care and designed the experimental protocols of the consortium.