New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

• Published in: Nature genetics Vol. 42; no. 2; pp. 105 - 116
• Main Authors: Jackson, Anne U, Wheeler, Eleanor, Bouatia-Naji, Nabila, Morris, Andrew P, Rybin, Denis, Thorleifsson, Gudmar, Steinthorsdottir, Valgerdur, Grallert, Harald, Dehghan, Abbas, Franklin, Christopher S, Song, Kijoung, Egan, Josephine M, Lajunen, Taina, Doney, Alex, Kanoni, Stavroula, Qi, Lu, Gieger, Christian, Payne, Felicity, Roccasecca, Rosa Maria, Sethupathy, Praveen, Balkau, Beverley, Barter, Philip, Beilby, John P, Benediktsson, Rafn, Bergmann, Sven, Bumpstead, Suzannah J, Chines, Peter, Cornelis, Marilyn, Day, Ian N M, de Geus, Eco J C, Dina, Christian, Erdos, Michael R, Fedson, Annette C, Fischer-Rosinsky, Antje, Graessler, Jürgen, Grundy, Scott, Hartikainen, Anna-Liisa, Hassanali, Neelam, Hayward, Caroline, Heath, Simon C, Herder, Christian, Hicks, Andrew A, Hillman, David R, Hingorani, Aroon D, Hui, Jennie, Isomaa, Bo, Johnson, Paul R V, Jula, Antti, Kaakinen, Marika, Kesaniemi, Y Antero, Kivimaki, Mika, Knight, Beatrice, Mahley, Robert, Mangino, Massimo, McAteer, Jarred B, McPherson, Ruth, Morken, Mario A, Mukherjee, Sutapa, Naitza, Silvia, Narisu, Narisu, Pattaro, Cristian, Pedersen, Nancy L, Pichler, Irene, Polasek, Ozren, Posthuma, Danielle, Province, Michael A, Psaty, Bruce M, Roden, Michael, Sanna, Serena, Sayer, Avan Aihie, Scheet, Paul, Scott, Laura J, Seedorf, Udo, Shields, Beverley, Simpson, Laila, Swift, Amy, Syvänen, Ann-Christine, Tanaka, Toshiko, Thorand, Barbara, Tichet, Jean, Varma, Dhiraj, Vitart, Veronique, Waeber, Gérard, Walley, Andrew, Walters, G Bragi, Wild, Sarah H, Zelenika, Diana, Zhai, Guangju, Zillikens, M Carola, Meneton, Pierre, Magnusson, Patrik K E, Salomaa, Veikko, Schwarz, Peter, Karpe, Fredrik, Dedoussis, George V, Kuusisto, Johanna, Pedersen, Oluf, Pramstaller, Peter Paul, Wichmann, H Erich, Stumvoll, Michael
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2010; Nature Publishing Group
• Subjects: 631/208/727/2000; 631/208/729/743; 631/443/319/1642/137/773; Adolescent; Adult; Agriculture; Alleles; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Blood Glucose - genetics; Blood Glucose - metabolism; Cancer Research; Child; Clinical Medicine; Databases, Genetic; Delta-5 Fatty Acid Desaturase; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; DNA Copy Number Variations - genetics; Endocrine pancreas. Apud cells (diseases); Endocrinology and Diabetes; Endocrinopathies; Endokrinologi och diabetes; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fasting - blood; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Gene Function; Genetic aspects; Genetic Loci - genetics; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Glucose; Health aspects; Health risks; Homeostasis; Homeostasis - genetics; Human Genetics; Humans; Hyperglycemia; Insulin; Klinisk medicin; Life Sciences; Medical and Health Sciences; Medical sciences; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Meta-analysis; Meta-Analysis as Topic; Physiological aspects; Polymorphism, Single Nucleotide - genetics; Quantitative Trait Loci - genetics; Quantitative Trait, Heritable; Reproducibility of Results; Risk factors; Sample size; Studies; Type 2 diabetes; United Kingdom; Netherlands; Sweden; Endocrinopathy; Type 2 diabetes; Homeostasis; Metabolic diseases; Genetics; Risk; Glucose; Locus
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.520

The MAGIC investigators report results of a large genome-wide association study meta-analysis to identify common variants influencing fasting glucose homeostasis. They further show that several of the newly discovered loci influencing glycemic traits are also associated with risk of type 2 diabetes. Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5 , MADD , ADRA2A , CRY2 , FADS1 , GLIS3 , SLC2A2 , PROX1 and C2CD4B ) and one influencing fasting insulin and HOMA-IR (near IGF1 ). We also demonstrated association of ADCY5 , PROX1 , GCK , GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.