TY - JOUR
T1 - New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk
AU - DIAGRAM Consortium
AU - Dupuis, Josée
AU - Langenberg, Claudia
AU - Prokopenko, Inga
AU - Saxena, Richa
AU - Soranzo, Nicole
AU - Jackson, Anne U
AU - Wheeler, Eleanor
AU - Glazer, Nicole L
AU - Bouatia-Naji, Nabila
AU - Gloyn, Anna L
AU - Lindgren, Cecilia M
AU - Mägi, Reedik
AU - Morris, Andrew P
AU - Randall, Joshua
AU - Johnson, Toby
AU - Elliott, Paul
AU - Rybin, Denis
AU - Thorleifsson, Gudmar
AU - Steinthorsdottir, Valgerdur
AU - Henneman, Peter
AU - Grallert, Harald
AU - Dehghan, Abbas
AU - Hottenga, Jouke Jan
AU - Franklin, Christopher S
AU - Navarro, Pau
AU - Song, Kijoung
AU - Goel, Anuj
AU - Perry, John R B
AU - Egan, Josephine M
AU - Lajunen, Taina
AU - Grarup, Niels
AU - Sparsø, Thomas
AU - Doney, Alex
AU - Voight, Benjamin F
AU - Stringham, Heather M
AU - Li, Man
AU - Kanoni, Stavroula
AU - Shrader, Peter
AU - Cavalcanti-Proença, Christine
AU - Kumari, Meena
AU - Qi, Lu
AU - Timpson, Nicholas J
AU - Hayward, Caroline
AU - Vitart, Veronique
AU - Wild, Sarah H
AU - Morris, Andrew
AU - Rudan, Igor
AU - Wright, Alan F
AU - Campbell, Harry
AU - Wilson, James F
PY - 2010/2
Y1 - 2010/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=75749086085&partnerID=8YFLogxK
U2 - 10.1038/ng.520
DO - 10.1038/ng.520
M3 - Article
C2 - 20081858
SN - 1546-1718
VL - 42
SP - 105
EP - 116
JO - Nature Genetics
JF - Nature Genetics
IS - 2
ER -