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

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

1822 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

Adgang til dokumentet

10.1038/ng.520

Citationsformater

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 Genetics

JF - Nature Genetics

IS - 2

ER -