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

Josée Dupuis; Claudia Langenberg; Inga Prokopenko; Richa Saxena; Nicole Soranzo; Anne U Jackson; Eleanor Wheeler; Nicole L Glazer; Nabila Bouatia-Naji; Anna L Gloyn; Cecilia M Lindgren; Reedik Mägi; Andrew P Morris; Joshua Randall; Toby Johnson; Paul Elliott; Denis Rybin; Gudmar Thorleifsson; Valgerdur Steinthorsdottir; Peter Henneman; Harald Grallert; Abbas Dehghan; Jouke Jan Hottenga; Christopher S Franklin; Pau Navarro; Kijoung Song; Anuj Goel; John R B Perry; Josephine M Egan; Taina Lajunen; Niels Grarup; Thomas Sparsø; Alex Doney; Benjamin F Voight; Heather M Stringham; Man Li; Stavroula Kanoni; Peter Shrader; Christine Cavalcanti-Proença; Meena Kumari; Lu Qi; Nicholas J Timpson; Christian Gieger; Carina Zabena; Ghislain Rocheleau; Erik Ingelsson; Ping An; Torben Jørgensen; Torben Hansen; Oluf Pedersen; DIAGRAM Consortium

doi:10.1038/ng.520

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

Josée Dupuis, Claudia Langenberg, Inga Prokopenko, Richa Saxena, Nicole Soranzo, Anne U Jackson, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Anna L Gloyn, Cecilia M Lindgren, Reedik Mägi, Andrew P Morris, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Gudmar Thorleifsson, Valgerdur Steinthorsdottir, Peter HennemanHarald Grallert, Abbas Dehghan, Jouke Jan Hottenga, Christopher S Franklin, Pau Navarro, Kijoung Song, Anuj Goel, John R B Perry, Josephine M Egan, Taina Lajunen, Niels Grarup, Thomas Sparsø, Alex Doney, Benjamin F Voight, Heather M Stringham, Man Li, Stavroula Kanoni, Peter Shrader, Christine Cavalcanti-Proença, Meena Kumari, Lu Qi, Nicholas J Timpson, Christian Gieger, Carina Zabena, Ghislain Rocheleau, Erik Ingelsson, Ping An, Torben Jørgensen, Torben Hansen, Oluf Pedersen, DIAGRAM Consortium

1496 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	42
Udgave nummer	2
Sider (fra-til)	105-16
Antal sider	12
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.520
Status	Udgivet - 1 feb. 2010

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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., Elliott, P., Rybin, D., Thorleifsson, G., Steinthorsdottir, V., ... DIAGRAM Consortium (2010). New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nature Genetics, 42(2), 105-16. https://doi.org/10.1038/ng.520

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, Elliott, P, Rybin, D, Thorleifsson, G, Steinthorsdottir, V, Henneman, P, Grallert, H, Dehghan, A, Hottenga, JJ, Franklin, CS, Navarro, P, Song, K, Goel, A, Perry, JRB, Egan, JM, Lajunen, T, Grarup, N, Sparsø, T, Doney, A, Voight, BF, Stringham, HM, Li, M, Kanoni, S, Shrader, P, Cavalcanti-Proença, C, Kumari, M, Qi, L, Timpson, NJ, Gieger, C, Zabena, C, Rocheleau, G, Ingelsson, E, An, P, Jørgensen, T, Hansen, T , Pedersen, O & DIAGRAM Consortium 2010, 'New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk', Nature Genetics, bind 42, nr. 2, s. 105-16. 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.",

keywords = "Adolescent, Adult, Alleles, Blood Glucose, Child, DNA Copy Number Variations, Databases, Genetic, Diabetes Mellitus, Type 2, Fasting, Gene Expression Regulation, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeostasis, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Reproducibility of Results",

author = "Jos{\'e}e Dupuis and Claudia Langenberg and Inga Prokopenko and Richa Saxena and Nicole Soranzo and Jackson, {Anne U} and Eleanor Wheeler and Glazer, {Nicole L} and Nabila Bouatia-Naji and Gloyn, {Anna L} and Lindgren, {Cecilia M} and Reedik M{\"a}gi and Morris, {Andrew P} and Joshua Randall and Toby Johnson and Paul Elliott and Denis Rybin and Gudmar Thorleifsson and Valgerdur Steinthorsdottir and Peter Henneman and Harald Grallert and Abbas Dehghan and Hottenga, {Jouke Jan} and Franklin, {Christopher S} and Pau Navarro and Kijoung Song and Anuj Goel and Perry, {John R B} and Egan, {Josephine M} and Taina Lajunen and Niels Grarup and Thomas Spars{\o} and Alex Doney and Voight, {Benjamin F} and Stringham, {Heather M} and Man Li and Stavroula Kanoni and Peter Shrader and Christine Cavalcanti-Proen{\c c}a and Meena Kumari and Lu Qi and Timpson, {Nicholas J} and Christian Gieger and Carina Zabena and Ghislain Rocheleau and Erik Ingelsson and Ping An and Torben J{\o}rgensen and Torben Hansen and Oluf Pedersen and {DIAGRAM Consortium}",

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

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 - Gieger, Christian

AU - Zabena, Carina

AU - Rocheleau, Ghislain

AU - Ingelsson, Erik

AU - An, Ping

AU - Jørgensen, Torben

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - DIAGRAM Consortium

PY - 2010/2/1

Y1 - 2010/2/1

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.

KW - Adolescent

KW - Adult

KW - Alleles

KW - Blood Glucose

KW - Child

KW - DNA Copy Number Variations

KW - Databases, Genetic

KW - Diabetes Mellitus, Type 2

KW - Fasting

KW - Gene Expression Regulation

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Homeostasis

KW - Humans

KW - Meta-Analysis as Topic

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

KW - Quantitative Trait, Heritable

KW - Reproducibility of Results

U2 - 10.1038/ng.520

DO - 10.1038/ng.520

M3 - Journal article

C2 - 20081858

SN - 1061-4036

VL - 42

SP - 105

EP - 116

JO - Nature: New biology

JF - Nature: New biology

IS - 2

ER -

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

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