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

Josee 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 Magi; 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 Sparso; Alex Doney; Benjamin F. Voight; Heather M. Stringham; Man Li; Stavroula Kanoni; Peter Shrader; Christine Cavalcanti-Proenca; Meena Kumari; Lu Qi; Nicholas J. Timpson; Yoav Ben-Shlomo; Ian N. M. Day; Paul R. V. Johnson; Mika Kivimaki; Debbie A. Lawlor; George Davey Smith; Lyle J. Palmer; Shah Ebrahim; DIAGRAM Consortium; GIANT Consortium; Global BPgen Consortium; Anders Hamsten Procardis Consortiu; MAGIC Investigators

doi:10.1038/ng.520

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

Josee 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 Magi, 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 Sparso, Alex Doney, Benjamin F. Voight, Heather M. Stringham, Man Li, Stavroula Kanoni, Peter Shrader, Christine Cavalcanti-Proenca, Meena Kumari, Lu Qi, Nicholas J. Timpson, Yoav Ben-Shlomo, Ian N. M. Day, Paul R. V. Johnson, Mika Kivimaki, Debbie A. Lawlor, George Davey Smith, Lyle J. Palmer, Shah Ebrahim, DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium, Anders Hamsten Procardis Consortiu, MAGIC Investigators

Research output: Contribution to journal › Article (Academic Journal) › peer-review

1573 Citations (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.

Original language	English
Pages (from-to)	105-U32
Number of pages	15
Journal	Nature Genetics
Volume	42
Issue number	2
DOIs	https://doi.org/10.1038/ng.520
Publication status	Published - Feb 2010

Keywords

GENOME-WIDE ASSOCIATION
BETA-CELL DYSFUNCTION
PLASMA-GLUCOSE
INSULIN-SECRETION
TRIGLYCERIDE LEVELS
ESSENTIAL COMPONENTS
MODEL ASSESSMENT
COMMON VARIANTS
CIRCADIAN CLOCK
DISEASE RISK

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10.1038/ng.520

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Davey Smith, G.
1/09/07 → 1/09/13
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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., Magi, R., Morris, A. P., Randall, J., Johnson, T., Elliott, P., Rybin, D., Thorleifsson, G., Steinthorsdottir, V., ... MAGIC Investigators (2010). New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nature Genetics, 42(2), 105-U32. https://doi.org/10.1038/ng.520

Dupuis, Josee ; 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. ; Magi, 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 R. B. ; Egan, Josephine M. ; Lajunen, Taina ; Grarup, Niels ; Sparso, Thomas ; Doney, Alex ; Voight, Benjamin F. ; Stringham, Heather M. ; Li, Man ; Kanoni, Stavroula ; Shrader, Peter ; Cavalcanti-Proenca, Christine ; Kumari, Meena ; Qi, Lu ; Timpson, Nicholas J. ; Ben-Shlomo, Yoav ; Day, Ian N. M. ; Johnson, Paul R. V. ; Kivimaki, Mika ; Lawlor, Debbie A. ; Smith, George Davey ; Palmer, Lyle J. ; Ebrahim, Shah ; DIAGRAM Consortium ; GIANT Consortium ; Global BPgen Consortium ; Anders Hamsten Procardis Consortiu ; MAGIC Investigators. / New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. In: Nature Genetics. 2010 ; Vol. 42, No. 2. pp. 105-U32.

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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 = "GENOME-WIDE ASSOCIATION, BETA-CELL DYSFUNCTION, PLASMA-GLUCOSE, INSULIN-SECRETION, TRIGLYCERIDE LEVELS, ESSENTIAL COMPONENTS, MODEL ASSESSMENT, COMMON VARIANTS, CIRCADIAN CLOCK, DISEASE RISK",

author = "Josee 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 Magi 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 Sparso and Alex Doney and Voight, {Benjamin F.} and Stringham, {Heather M.} and Man Li and Stavroula Kanoni and Peter Shrader and Christine Cavalcanti-Proenca and Meena Kumari and Lu Qi and Timpson, {Nicholas J.} and Yoav Ben-Shlomo and Day, {Ian N. M.} and Johnson, {Paul R. V.} and Mika Kivimaki and Lawlor, {Debbie A.} and Smith, {George Davey} and Palmer, {Lyle J.} and Shah Ebrahim and {DIAGRAM Consortium} and {GIANT Consortium} and {Global BPgen Consortium} and {Anders Hamsten Procardis Consortiu} and {MAGIC Investigators}",

year = "2010",

month = feb,

doi = "10.1038/ng.520",

language = "English",

volume = "42",

pages = "105--U32",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Springer Nature",

number = "2",

}

Dupuis, J, Langenberg, C, Prokopenko, I, Saxena, R, Soranzo, N, Jackson, AU, Wheeler, E, Glazer, NL, Bouatia-Naji, N, Gloyn, AL, Lindgren, CM, Magi, 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, Sparso, T, Doney, A, Voight, BF, Stringham, HM, Li, M, Kanoni, S, Shrader, P, Cavalcanti-Proenca, C, Kumari, M, Qi, L, Timpson, NJ , Ben-Shlomo, Y, Day, INM, Johnson, PRV, Kivimaki, M, Lawlor, DA , Smith, GD, Palmer, LJ, Ebrahim, S, DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium, Anders Hamsten Procardis Consortiu & MAGIC Investigators 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-U32. https://doi.org/10.1038/ng.520

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. / Dupuis, Josee; 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.; Magi, 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 R. B.; Egan, Josephine M.; Lajunen, Taina; Grarup, Niels; Sparso, Thomas; Doney, Alex; Voight, Benjamin F.; Stringham, Heather M.; Li, Man; Kanoni, Stavroula; Shrader, Peter; Cavalcanti-Proenca, Christine; Kumari, Meena; Qi, Lu; Timpson, Nicholas J.; Ben-Shlomo, Yoav; Day, Ian N. M.; Johnson, Paul R. V.; Kivimaki, Mika; Lawlor, Debbie A.; Smith, George Davey; Palmer, Lyle J.; Ebrahim, Shah; DIAGRAM Consortium; GIANT Consortium; Global BPgen Consortium; Anders Hamsten Procardis Consortiu; MAGIC Investigators.

In: Nature Genetics, Vol. 42, No. 2, 02.2010, p. 105-U32.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

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

AU - Dupuis, Josee

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 - Magi, 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 - Sparso, Thomas

AU - Doney, Alex

AU - Voight, Benjamin F.

AU - Stringham, Heather M.

AU - Li, Man

AU - Kanoni, Stavroula

AU - Shrader, Peter

AU - Cavalcanti-Proenca, Christine

AU - Kumari, Meena

AU - Qi, Lu

AU - Timpson, Nicholas J.

AU - Ben-Shlomo, Yoav

AU - Day, Ian N. M.

AU - Johnson, Paul R. V.

AU - Kivimaki, Mika

AU - Lawlor, Debbie A.

AU - Smith, George Davey

AU - Palmer, Lyle J.

AU - Ebrahim, Shah

AU - DIAGRAM Consortium

AU - GIANT Consortium

AU - Global BPgen Consortium

AU - Anders Hamsten Procardis Consortiu

AU - MAGIC Investigators

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.

KW - GENOME-WIDE ASSOCIATION

KW - BETA-CELL DYSFUNCTION

KW - PLASMA-GLUCOSE

KW - INSULIN-SECRETION

KW - TRIGLYCERIDE LEVELS

KW - ESSENTIAL COMPONENTS

KW - MODEL ASSESSMENT

KW - COMMON VARIANTS

KW - CIRCADIAN CLOCK

KW - DISEASE RISK

U2 - 10.1038/ng.520

DO - 10.1038/ng.520

M3 - Article (Academic Journal)

C2 - 20081858

VL - 42

SP - 105-U32

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 2

ER -

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

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