Billings, L.K. & Florez, J.C. The genetics of type 2 diabetes: what have we learned from GWAS? Ann. NY Acad. Sci. 1212, 59–77 (2010).
Sladek, R. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007).
Dupuis, J. et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105–116 (2010).
Voight, B.F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42, 579–589 (2010).
Prudente, S., Morini, E. & Trischitta, V. Insulin signaling regulating genes: effect on T2DM and cardiovascular risk. Nat. Rev. Endocrinol. 5, 682–693 (2009).
Kahn, S.E., Hull, R.L. & Utzschneider, K.M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006).
Wang, X. et al. Heritability of insulin sensitivity and lipid profile depend on BMI: evidence for gene-obesity interaction. Diabetologia 52, 2578–2584 (2009).
Florez, J.C. et al. Effects of the type 2 diabetes–associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone. J. Clin. Endocrinol. Metab. 92, 1502–1509 (2007).
Ludovico, O. et al. Heterogeneous effect of peroxisome proliferator–activated receptor γ2 Ala12 variant on type 2 diabetes risk. Obesity (Silver Spring) 15, 1076–1081 (2007).
Cauchi, S. et al. The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies. BMC Med. Genet. 9, 45 (2008).
Trujillo, M.E. & Scherer, P.E. Adipose tissue–derived factors: impact on health and disease. Endocr. Rev. 27, 762–778 (2006).
Shoelson, S.E., Lee, J. & Goldfine, A.B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 (2006).
Kraft, P., Yen, Y.C., Stram, D.O., Morrison, J. & Gauderman, W.J. Exploiting gene-environment interaction to detect genetic associations. Hum. Hered. 63, 111–119 (2007).
Manning, A.K. et al. Meta-analysis of gene-environment interaction: joint estimation of SNP and SNP × environment regression coefficients. Genet. Epidemiol. 35, 11–18 (2011).
Matthews, D.R. et al. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412–419 (1985).
Speliotes, E.K. et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937–948 (2010).
Heid, I.M. et al. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat. Genet. 42, 949–960 (2010).
Teslovich, T.M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).
Rampersaud, E. et al. Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the Old Order Amish: evidence for replication from diabetes-related quantitative traits and from independent populations. Diabetes 56, 3053–3062 (2007).
Stolerman, E.S. et al. Haplotype structure of the ENPP1 gene and nominal association of the K121Q missense single nucleotide polymorphism with glycemic traits in the Framingham Heart Study. Diabetes 57, 1971–1977 (2008).
Dehghan, A. et al. Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation 123, 731–738 (2011).
Hivert, M.F. et al. Insulin resistance influences the association of adiponectin levels with diabetes incidence in two population-based cohorts: the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 study and the Framingham Offspring Study. Diabetologia 54, 1019–1024 (2011).
Florez, J.C. Newly identified loci highlight β cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes? Diabetologia 51, 1100–1110 (2008).
Timpson, N.J. et al. Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data. Diabetes 58, 505–510 (2009).
Skol, A.D., Scott, L.J., Abecasis, G.R. & Boehnke, M. Optimal designs for two-stage genome-wide association studies. Genet. Epidemiol. 31, 776–788 (2007).
Skol, A.D., Scott, L.J., Abecasis, G.R. & Boehnke, M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat. Genet. 38, 209–213 (2006).
Saxena, R. et al. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat. Genet. 42, 142–148 (2010).
Soranzo, N. et al. Common variants at 10 genomic loci influence hemoglobin A1C levels via glycemic and nonglycemic pathways. Diabetes 59, 3229–3239 (2010).
Strawbridge, R.J. et al. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes. Diabetes 60, 2624–2634 (2011).
Lango Allen, H. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010).
Carroll, E.A. et al. Cordon-bleu is a conserved gene involved in neural tube formation. Dev. Biol. 262, 16–31 (2003).
Depetris, R.S. et al. Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14. Mol. Cell 20, 325–333 (2005).
Ridker, P.M. et al. Polymorphism in the CETP gene region, HDL cholesterol, and risk of future myocardial infarction: genomewide analysis among 18 245 initially healthy women from the Women's Genome Health Study. Circ. Cardiovasc. Genet. 2, 26–33 (2009).
White, M.F. The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol. Cell. Biochem. 182, 3–11 (1998).
Rung, J. et al. Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat. Genet. 41, 1110–1115 (2009).
Samani, N.J. et al. Genomewide association analysis of coronary artery disease. N. Engl. J. Med. 357, 443–453 (2007).
Waterworth, D.M. et al. Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 30, 2264–2276 (2010).
Schadt, E.E. et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008).
Smith, S., Giriat, I., Schmitt, A. & de Lange, T. Tankyrase, a poly(ADP-ribose) polymerase at human telomeres. Science 282, 1484–1487 (1998).
Chi, N.W. & Lodish, H.F. Tankyrase is a golgi-associated mitogen-activated protein kinase substrate that interacts with IRAP in GLUT4 vesicles. J. Biol. Chem. 275, 38437–38444 (2000).
Huang, S.M. et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461, 614–620 (2009).
Royce, P.M. & Steinmann, B. Prolidase deficiency. Connective Tissue and Its Heritable Disorders 727–743 (Wiley-Liss, New York, 2002).
Nica, A.C. et al. The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. PLoS Genet. 7, e1002003 (2011).
The ARIC investigators. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. Am. J. Epidemiol. 129, 687–702 (1989).
Bostick, M. et al. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317, 1760–1764 (2007).
Ng, P.C. & Henikoff, S. Predicting deleterious amino acid substitutions. Genome Res. 11, 863–874 (2001).
Evans, R.M., Barish, G.D. & Wang, Y.X. PPARs and the complex journey to obesity. Nat. Med. 10, 355–361 (2004).
Reigstad, L.J. et al. Platelet-derived growth factor (PDGF)-C, a PDGF family member with a vascular endothelial growth factor–like structure. J. Biol. Chem. 278, 17114–17120 (2003).
Handford, C.A. et al. The human glycine receptor β subunit: primary structure, functional characterisation and chromosomal localisation of the human and murine genes. Brain Res. Mol. Brain Res. 35, 211–219 (1996).
den Hoed, M. et al. Genetic susceptibility to obesity and related traits in childhood and adolescence: influence of loci identified by genome-wide association studies. Diabetes 59, 2980–2988 (2010).
Hotta, K. et al. Polymorphisms in NRXN3, TFAP2B, MSRA, LYPLAL1, FTO and MC4R and their effect on visceral fat area in the Japanese population. J. Hum. Genet. 55, 738–742 (2010).
Lindgren, C.M. et al. Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution. PLoS Genet. 5, e1000508 (2009).
Seve, M., Chimienti, F., Devergnas, S. & Favier, A. In silico identification and expression of SLC30 family genes: an expressed sequence tag data mining strategy for the characterization of zinc transporters' tissue expression. BMC Genomics 5, 32 (2004).
Ohagi, S. et al. Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM. Diabetes 45, 897–901 (1996).
Benzinou, M. et al. Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat. Genet. 40, 943–945 (2008).
Miura, K. et al. ARAP1: a point of convergence for Arf and Rho signaling. Mol. Cell 9, 109–119 (2002).
Clément, S. et al. The lipid phosphatase SHIP2 controls insulin sensitivity. Nature 409, 92–97 (2001).
Kent, W.J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002).
Silva, J.P. et al. Regulation of adaptive behaviour during fasting by hypothalamic Foxa2. Nature 462, 646–650 (2009).
Xing, C., Cohen, J.C. & Boerwinkle, E. A weighted false discovery rate control procedure reveals alleles at FOXA2 that influence fasting glucose levels. Am. J. Hum. Genet. 86, 440–446 (2010).
Liu, F. & Roth, R.A. Grb-IR: a SH2-domain-containing protein that binds to the insulin receptor and inhibits its function. Proc. Natl. Acad. Sci. USA 92, 10287–10291 (1995).
Giovannone, B. et al. Two novel proteins that are linked to insulin-like growth factor (IGF-I) receptors by the Grb10 adapter and modulate IGF-I signaling. J. Biol. Chem. 278, 31564–31573 (2003).
Murray, M.V., Kobayashi, R. & Krainer, A.R. The type 2C Ser/Thr phosphatase PP2Cγ is a pre-mRNA splicing factor. Genes Dev. 13, 87–97 (1999).
Schwitzgebel, V.M. et al. Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1. J. Clin. Endocrinol. Metab. 88, 4398–4406 (2003).
Stoffers, D.A., Ferrer, J., Clarke, W.L. & Habener, J.F. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat. Genet. 17, 138–139 (1997).
Cockburn, B.N. et al. Insulin promoter factor–1 mutations and diabetes in Trinidad: identification of a novel diabetes-associated mutation (E224K) in an Indo-Trinidadian family. J. Clin. Endocrinol. Metab. 89, 971–978 (2004).
Rasmussen-Torvik, L.J. et al. Impact of repeated measures and sample selection on genome-wide association studies of fasting glucose. Genet. Epidemiol. 34, 665–673 (2010).
Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).
Li, Y., Willer, C.J., Ding, J., Scheet, P. & Abecasis, G.R. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010).
Howie, B.N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).
Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).
Voorman, A., Lumley, T., McKnight, B. & Rice, K. Behavior of QQ-plots and genomic control in studies of gene-environment interaction. PLoS ONE 6, e19416 (2011).
Aulchenko, Y.S., Struchalin, M.V. & van Duijn, C.M. ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics 11, 134 (2010).
Petitti, D.B. Statistical methods in meta-analysis. in Meta-analysis, Decision Analysis, and Cost-effectiveness Analysis 90–114 (Oxford University Press, New York, 1994).
Higgins, J.P. & Thompson, S.G. Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).
The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).
Riva, A. & Kohane, I.S. A SNP-centric database for the investigation of the human genome. BMC Bioinformatics 5, 33 (2004).
The Wellcome Trust Case Control Consortium. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464, 713–720 (2010).
McCarroll, S.A. et al. Common deletion polymorphisms in the human genome. Nat. Genet. 38, 86–92 (2006).