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

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abstract

  • 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.

authors

  • Dupuis, Josée
  • Langenberg, Claudia
  • Prokopenko, Inga
  • Saxena, Richa
  • Soranzo, Nicole
  • Jackson, Anne U
  • Wheeler, Eleanor
  • Glazer, Nicole L
  • Bouatia-Naji, Nabila
  • Gloyn, Anna L
  • Lindgren, Cecilia M
  • Mägi, Reedik
  • Morris, Andrew P
  • Randall, Joshua
  • Johnson, Toby
  • Elliott, Paul
  • Rybin, Denis
  • Thorleifsson, Gudmar
  • Steinthorsdottir, Valgerdur
  • Henneman, Peter
  • Grallert, Harald
  • Dehghan, Abbas
  • Hottenga, Jouke Jan
  • Franklin, Christopher S
  • Navarro, Pau
  • Song, Kijoung
  • Goel, Anuj
  • Perry, John RB
  • Egan, Josephine M
  • Lajunen, Taina
  • Grarup, Niels
  • Sparsø, Thomas
  • Doney, Alex
  • Voight, Benjamin F
  • Stringham, Heather M
  • Li, Man
  • Kanoni, Stavroula
  • Shrader, Peter
  • Cavalcanti-Proença, Christine
  • Kumari, Meena
  • Qi, Lu
  • Timpson, Nicholas J
  • Gieger, Christian
  • Zabena, Carina
  • Rocheleau, Ghislain
  • Ingelsson, Erik
  • An, Ping
  • O'Connell, Jeffrey
  • Luan, Jian'an
  • Elliott, Amanda
  • McCarroll, Steven A
  • Payne, Felicity
  • Roccasecca, Rosa Maria
  • Pattou, François
  • Sethupathy, Praveen
  • Ardlie, Kristin
  • Ariyurek, Yavuz
  • Balkau, Beverley
  • Barter, Philip
  • Beilby, John P
  • Ben-Shlomo, Yoav
  • Benediktsson, Rafn
  • Bennett, Amanda J
  • Bergmann, Sven
  • Bochud, Murielle
  • Boerwinkle, Eric
  • Bonnefond, Amélie
  • Bonnycastle, Lori L
  • Borch-Johnsen, Knut
  • Böttcher, Yvonne
  • Brunner, Eric
  • Bumpstead, Suzannah J
  • Charpentier, Guillaume
  • Chen, Yii-Der Ida
  • Chines, Peter
  • Clarke, Robert
  • Coin, Lachlan JM
  • Cooper, Matthew N
  • Cornelis, Marilyn
  • Crawford, Gabe
  • Crisponi, Laura
  • Day, Ian NM
  • de Geus, Eco JC
  • Delplanque, Jerome
  • Dina, Christian
  • Erdos, Michael R
  • Fedson, Annette C
  • Fischer-Rosinsky, Antje
  • Forouhi, Nita G
  • Fox, Caroline S
  • Frants, Rune
  • Franzosi, Maria Grazia
  • Galan, Pilar
  • Goodarzi, Mark O
  • Graessler, Jürgen
  • Groves, Christopher J
  • Grundy, Scott
  • Gwilliam, Rhian
  • Gyllensten, Ulf
  • Hadjadj, Samy
  • Hallmans, Göran
  • Hammond, Naomi
  • Han, Xijing
  • Hartikainen, Anna-Liisa
  • Hassanali, Neelam
  • Hayward, Caroline
  • Heath, Simon C
  • Hercberg, Serge
  • Herder, Christian
  • Hicks, Andrew A
  • Hillman, David R
  • Hingorani, Aroon D
  • Hofman, Albert
  • Hui, Jennie
  • Hung, Joe
  • Isomaa, Bo
  • Johnson, Paul RV
  • Jørgensen, Torben
  • Jula, Antti
  • Kaakinen, Marika
  • Kaprio, Jaakko
  • Kesaniemi, Y Antero
  • Kivimaki, Mika
  • Knight, Beatrice
  • Koskinen, Seppo
  • Kovacs, Peter
  • Kyvik, Kirsten Ohm
  • Lathrop, G Mark
  • Lawlor, Debbie A
  • Le Bacquer, Olivier
  • Lecoeur, Cécile
  • Li, Yun
  • Lyssenko, Valeriya
  • Mahley, Robert
  • Mangino, Massimo
  • Manning, Alisa K
  • Martínez-Larrad, María Teresa
  • McAteer, Jarred B
  • McCulloch, Laura J
  • McPherson, Ruth
  • Meisinger, Christa
  • Melzer, David
  • Meyre, David Jean-Claude
  • Mitchell, Braxton D
  • Morken, Mario A
  • Mukherjee, Sutapa
  • Naitza, Silvia
  • Narisu, Narisu
  • Neville, Matthew J
  • Oostra, Ben A
  • Orrù, Marco
  • Pakyz, Ruth
  • Palmer, Colin NA
  • Paolisso, Giuseppe
  • Pattaro, Cristian
  • Pearson, Daniel
  • Peden, John F
  • Pedersen, Nancy L
  • Perola, Markus
  • Pfeiffer, Andreas FH
  • Pichler, Irene
  • Polasek, Ozren
  • Posthuma, Danielle
  • Potter, Simon C
  • Pouta, Anneli
  • Province, Michael A
  • Psaty, Bruce M
  • Rathmann, Wolfgang
  • Rayner, Nigel W
  • Rice, Kenneth
  • Ripatti, Samuli
  • Rivadeneira, Fernando
  • Roden, Michael
  • Rolandsson, Olov
  • Sandbaek, Annelli
  • Sandhu, Manjinder
  • Sanna, Serena
  • Sayer, Avan Aihie
  • Scheet, Paul
  • Scott, Laura J
  • Seedorf, Udo
  • Sharp, Stephen J
  • Shields, Beverley
  • Sigurðsson, Gunnar
  • Sijbrands, Eric JG
  • Silveira, Angela
  • Simpson, Laila
  • Singleton, Andrew
  • Smith, Nicholas L
  • Sovio, Ulla
  • Swift, Amy
  • Syddall, Holly
  • Syvänen, Ann-Christine
  • Tanaka, Toshiko
  • Thorand, Barbara
  • Tichet, Jean
  • Tönjes, Anke
  • Tuomi, Tiinamaija
  • Uitterlinden, André G
  • van Dijk, Ko Willems
  • van Hoek, Mandy
  • Varma, Dhiraj
  • Visvikis-Siest, Sophie
  • Vitart, Veronique
  • Vogelzangs, Nicole
  • Waeber, Gérard
  • Wagner, Peter J
  • Walley, Andrew
  • Walters, G Bragi
  • Ward, Kim L
  • Watkins, Hugh
  • Weedon, Michael N
  • Wild, Sarah H
  • Willemsen, Gonneke
  • Witteman, Jaqueline CM
  • Yarnell, John WG
  • Zeggini, Eleftheria
  • Zelenika, Diana
  • Zethelius, Björn
  • Zhai, Guangju
  • Zhao, Jing Hua
  • Zillikens, M Carola
  • Borecki, Ingrid B
  • Loos, Ruth JF
  • Meneton, Pierre
  • Magnusson, Patrik KE
  • Nathan, David M
  • Williams, Gordon H
  • Hattersley, Andrew T
  • Silander, Kaisa
  • Salomaa, Veikko
  • Smith, George Davey
  • Bornstein, Stefan R
  • Schwarz, Peter
  • Spranger, Joachim
  • Karpe, Fredrik
  • Shuldiner, Alan R
  • Cooper, Cyrus
  • Dedoussis, George V
  • Serrano-Ríos, Manuel
  • Morris, Andrew D
  • Lind, Lars
  • Palmer, Lyle J
  • Hu, Frank B
  • Franks, Paul W
  • Ebrahim, Shah
  • Marmot, Michael
  • Kao, WH Linda
  • Pankow, James S
  • Sampson, Michael J
  • Kuusisto, Johanna
  • Laakso, Markku
  • Hansen, Torben
  • Pedersen, Oluf
  • Pramstaller, Peter Paul
  • Wichmann, H Erich
  • Illig, Thomas
  • Rudan, Igor
  • Wright, Alan F
  • Stumvoll, Michael
  • Campbell, Harry
  • Wilson, James F
  • Bergman, Richard N
  • Buchanan, Thomas A
  • Collins, Francis S
  • Mohlke, Karen L
  • Tuomilehto, Jaakko
  • Valle, Timo T
  • Altshuler, David
  • Rotter, Jerome I
  • Siscovick, David S
  • Penninx, Brenda WJH
  • Boomsma, Dorret I
  • Deloukas, Panos
  • Spector, Timothy D
  • Frayling, Timothy M
  • Ferrucci, Luigi
  • Kong, Augustine
  • Thorsteinsdottir, Unnur
  • Stefansson, Kari
  • van Duijn, Cornelia M
  • Aulchenko, Yurii S
  • Cao, Antonio
  • Scuteri, Angelo
  • Schlessinger, David
  • Uda, Manuela
  • Ruokonen, Aimo
  • Jarvelin, Marjo-Riitta
  • Waterworth, Dawn M
  • Vollenweider, Peter
  • Peltonen, Leena
  • Mooser, Vincent
  • Abecasis, Goncalo R
  • Wareham, Nicholas J
  • Sladek, Robert
  • Froguel, Philippe
  • Watanabe, Richard M
  • Meigs, James B
  • Groop, Leif
  • Boehnke, Michael
  • McCarthy, Mark I
  • Florez, Jose C
  • Barroso, Inês

publication date

  • February 2010

has subject area