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

J. Dupuis; C. Langenberg; I. Prokopenko; R. Saxena; N. Soranzo; A.U. Jackson; E. Wheeler; N.L. Glazer; N. Bouatia-Naji; A.L. Gloyn; C.M. Lindgren; R. Mägi; A.P. Morris; J. Randall; T. Johnson; J.J. Hottenga; E.J.C. de Geus; J. Kaprio; K.O. Kyvik; N.L. Pedersen; M. Perola; D. Posthuma; F. Rivadeneira; A.G. Uitterlinden; K. Willems van Dijk; M. van Hoek; N. Vogelzangs; G. Willemsen; J.C.M. Witteman; M.C. Zillikens; B.W.J.H. Penninx; D.I. Boomsma; C.M. van Duijn; Y.S. Aulchenko; D. Waterworth; P. Vollenweider; L. Peltonen; V. Mooser; G.R. Abecasis; N.J. Wareham; R. Sladek; P. Froguel; R.M. Watanabe; J.B. Meigs; L.C. Groop; M. Boehnke; M.I. McCarthy; J.C. Florez; I. Barroso

doi:https://doi.org/10.1038/ng.520

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

J. Dupuis, C. Langenberg, I. Prokopenko, R. Saxena, N. Soranzo, A.U. Jackson, E. Wheeler, N.L. Glazer, N. Bouatia-Naji, A.L. Gloyn, C.M. Lindgren, R. Mägi, A.P. Morris, J. Randall, T. Johnson, J.J. Hottenga, E.J.C. de Geus, J. Kaprio, K.O. Kyvik, N.L. PedersenM. Perola, D. Posthuma, F. Rivadeneira, A.G. Uitterlinden, K. Willems van Dijk, M. van Hoek, N. Vogelzangs, G. Willemsen, J.C.M. Witteman, M.C. Zillikens, B.W.J.H. Penninx, D.I. Boomsma, C.M. van Duijn, Y.S. Aulchenko, D. Waterworth, P. Vollenweider, L. Peltonen, V. Mooser, G.R. Abecasis, N.J. Wareham, R. Sladek, P. Froguel, R.M. Watanabe, J.B. Meigs, L.C. Groop, M. Boehnke, M.I. McCarthy, J.C. Florez, I. Barroso

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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.

Original language	English
Pages (from-to)	105-116
Journal	Nature Genetics
Volume	42
Issue number	2
DOIs	https://doi.org/10.1038/ng.520
Publication status	Published - 2010

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Cite this

Dupuis, J., Langenberg, C., Prokopenko, I., Saxena, R., Soranzo, N., Jackson, A. U., Wheeler, E., Glazer, N. L., Bouatia-Naji, N., Gloyn, A. L., Lindgren, C. M., Mägi, R., Morris, A. P., Randall, J., Johnson, T., Hottenga, J. J., de Geus, E. J. C., Kaprio, J., Kyvik, K. O., ... Barroso, I. (2010). New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nature Genetics, 42(2), 105-116. https://doi.org/10.1038/ng.520

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

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.",

author = "J. Dupuis and C. Langenberg and I. Prokopenko and R. Saxena and N. Soranzo and A.U. Jackson and E. Wheeler and N.L. Glazer and N. Bouatia-Naji and A.L. Gloyn and C.M. Lindgren and R. M{\"a}gi and A.P. Morris and J. Randall and T. Johnson and J.J. Hottenga and {de Geus}, E.J.C. and J. Kaprio and K.O. Kyvik and N.L. Pedersen and M. Perola and D. Posthuma and F. Rivadeneira and A.G. Uitterlinden and {Willems van Dijk}, K. and {van Hoek}, M. and N. Vogelzangs and G. Willemsen and J.C.M. Witteman and M.C. Zillikens and B.W.J.H. Penninx and D.I. Boomsma and {van Duijn}, C.M. and Y.S. Aulchenko and D. Waterworth and P. Vollenweider and L. Peltonen and V. Mooser and G.R. Abecasis and N.J. Wareham and R. Sladek and P. Froguel and R.M. Watanabe and J.B. Meigs and L.C. Groop and M. Boehnke and M.I. McCarthy and J.C. Florez and I. Barroso",

year = "2010",

doi = "https://doi.org/10.1038/ng.520",

language = "English",

volume = "42",

pages = "105--116",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

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Dupuis, J, Langenberg, C, Prokopenko, I, Saxena, R, Soranzo, N, Jackson, AU, Wheeler, E, Glazer, NL, Bouatia-Naji, N, Gloyn, AL, Lindgren, CM, Mägi, R, Morris, AP, Randall, J, Johnson, T, Hottenga, JJ, de Geus, EJC, Kaprio, J, Kyvik, KO, Pedersen, NL, Perola, M, Posthuma, D, Rivadeneira, F, Uitterlinden, AG, Willems van Dijk, K, van Hoek, M, Vogelzangs, N, Willemsen, G, Witteman, JCM, Zillikens, MC, Penninx, BWJH, Boomsma, DI, van Duijn, CM, Aulchenko, YS, Waterworth, D, Vollenweider, P, Peltonen, L, Mooser, V, Abecasis, GR, Wareham, NJ, Sladek, R, Froguel, P, Watanabe, RM, Meigs, JB, Groop, LC, Boehnke, M, McCarthy, MI, Florez, JC & Barroso, I 2010, 'New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk', Nature Genetics, vol. 42, no. 2, pp. 105-116. https://doi.org/10.1038/ng.520

TY - JOUR

T1 - New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

AU - Dupuis, J.

AU - Langenberg, C.

AU - Prokopenko, I.

AU - Saxena, R.

AU - Soranzo, N.

AU - Jackson, A.U.

AU - Wheeler, E.

AU - Glazer, N.L.

AU - Bouatia-Naji, N.

AU - Gloyn, A.L.

AU - Lindgren, C.M.

AU - Mägi, R.

AU - Morris, A.P.

AU - Randall, J.

AU - Johnson, T.

AU - Hottenga, J.J.

AU - de Geus, E.J.C.

AU - Kaprio, J.

AU - Kyvik, K.O.

AU - Pedersen, N.L.

AU - Perola, M.

AU - Posthuma, D.

AU - Rivadeneira, F.

AU - Uitterlinden, A.G.

AU - Willems van Dijk, K.

AU - van Hoek, M.

AU - Vogelzangs, N.

AU - Willemsen, G.

AU - Witteman, J.C.M.

AU - Zillikens, M.C.

AU - Penninx, B.W.J.H.

AU - Boomsma, D.I.

AU - van Duijn, C.M.

AU - Aulchenko, Y.S.

AU - Waterworth, D.

AU - Vollenweider, P.

AU - Peltonen, L.

AU - Mooser, V.

AU - Abecasis, G.R.

AU - Wareham, N.J.

AU - Sladek, R.

AU - Froguel, P.

AU - Watanabe, R.M.

AU - Meigs, J.B.

AU - Groop, L.C.

AU - Boehnke, M.

AU - McCarthy, M.I.

AU - Florez, J.C.

AU - Barroso, I.

PY - 2010

Y1 - 2010

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.

U2 - https://doi.org/10.1038/ng.520

DO - https://doi.org/10.1038/ng.520

M3 - Article

C2 - 20081858

SN - 1061-4036

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EP - 116

JO - Nature Genetics

JF - Nature Genetics

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