Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

Benjamin F Voight; Laura J Scott; Valgerdur Steinthorsdottir; Andrew P Morris; Christian Dina; Ryan P Welch; Eleftheria Zeggini; Cornelia Huth; Yurii S Aulchenko; Gudmar Thorleifsson; Laura J McCulloch; Teresa Ferreira; Harald Grallert; Najaf Amin; Guanming Wu; Cristen J Willer; Soumya Raychaudhuri; Steve A McCarroll; Claudia Langenberg; Oliver M Hofmann; Josée Dupuis; Lu Qi; Ayellet V Segrè; Mandy van Hoek; Pau Navarro; Kristin Ardlie; Beverley Balkau; Rafn Benediktsson; Amanda J Bennett; Roza Blagieva; Eric Boerwinkle; Lori L Bonnycastle; Kristina Bengtsson Boström; Bert Bravenboer; Suzannah Bumpstead; Noisël P Burtt; Guillaume Charpentier; Peter S Chines; Marilyn Cornelis; David J Couper; Gabe Crawford; Alex S F Doney; Katherine S Elliott; Amanda L Elliott; Michael R Erdos; Niels Grarup; Torben Jørgensen; Thomas Sparsø; Torben Hansen; Oluf Pedersen; MAGIC investigators

doi:10.1038/ng.609

Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Andrew P Morris, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Claudia Langenberg, Oliver M HofmannJosée Dupuis, Lu Qi, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noisël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, David J Couper, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Niels Grarup, Torben Jørgensen, Thomas Sparsø, Torben Hansen, Oluf Pedersen, MAGIC investigators

1332 Citations (Scopus)

Abstract

By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P 5 × 10 8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

Original language	English
Journal	Nature Genetics
Volume	42
Issue number	7
Pages (from-to)	579-89
Number of pages	11
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.609
Publication status	Published - 1 Jul 2010

Keywords

Blood Glucose
Diabetes Mellitus, Type 2
Dual-Specificity Phosphatases
Fasting
Gene Dosage
Gene Expression Profiling
Genetic Heterogeneity
Genetic Predisposition to Disease
Genome, Human
Genome-Wide Association Study
Hepatocyte Nuclear Factor 1-alpha
Humans
KCNQ1 Potassium Channel
Meta-Analysis as Topic
Mitogen-Activated Protein Kinase Phosphatases
Polymorphism, Single Nucleotide

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.609

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Voight, B. F., Scott, L. J., Steinthorsdottir, V., Morris, A. P., Dina, C., Welch, R. P., Zeggini, E., Huth, C., Aulchenko, Y. S., Thorleifsson, G., McCulloch, L. J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C. J., Raychaudhuri, S., McCarroll, S. A., Langenberg, C., ... MAGIC investigators (2010). Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nature Genetics, 42(7), 579-89. https://doi.org/10.1038/ng.609

Voight, BF, Scott, LJ, Steinthorsdottir, V, Morris, AP, Dina, C, Welch, RP, Zeggini, E, Huth, C, Aulchenko, YS, Thorleifsson, G, McCulloch, LJ, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, CJ, Raychaudhuri, S, McCarroll, SA, Langenberg, C, Hofmann, OM, Dupuis, J, Qi, L, Segrè, AV, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, AJ, Blagieva, R, Boerwinkle, E, Bonnycastle, LL, Bengtsson Boström, K, Bravenboer, B, Bumpstead, S, Burtt, NP, Charpentier, G, Chines, PS, Cornelis, M, Couper, DJ, Crawford, G, Doney, ASF, Elliott, KS, Elliott, AL, Erdos, MR, Grarup, N, Jørgensen, T, Sparsø, T, Hansen, T , Pedersen, O & MAGIC investigators 2010, 'Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis', Nature Genetics, vol. 42, no. 7, pp. 579-89. https://doi.org/10.1038/ng.609

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abstract = "By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P 5 × 10 8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.",

keywords = "Blood Glucose, Diabetes Mellitus, Type 2, Dual-Specificity Phosphatases, Fasting, Gene Dosage, Gene Expression Profiling, Genetic Heterogeneity, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Hepatocyte Nuclear Factor 1-alpha, Humans, KCNQ1 Potassium Channel, Meta-Analysis as Topic, Mitogen-Activated Protein Kinase Phosphatases, Polymorphism, Single Nucleotide",

author = "Voight, {Benjamin F} and Scott, {Laura J} and Valgerdur Steinthorsdottir and Morris, {Andrew P} and Christian Dina and Welch, {Ryan P} and Eleftheria Zeggini and Cornelia Huth and Aulchenko, {Yurii S} and Gudmar Thorleifsson and McCulloch, {Laura J} and Teresa Ferreira and Harald Grallert and Najaf Amin and Guanming Wu and Willer, {Cristen J} and Soumya Raychaudhuri and McCarroll, {Steve A} and Claudia Langenberg and Hofmann, {Oliver M} and Jos{\'e}e Dupuis and Lu Qi and Segr{\`e}, {Ayellet V} and {van Hoek}, Mandy and Pau Navarro and Kristin Ardlie and Beverley Balkau and Rafn Benediktsson and Bennett, {Amanda J} and Roza Blagieva and Eric Boerwinkle and Bonnycastle, {Lori L} and {Bengtsson Bostr{\"o}m}, Kristina and Bert Bravenboer and Suzannah Bumpstead and Burtt, {Nois{\"e}l P} and Guillaume Charpentier and Chines, {Peter S} and Marilyn Cornelis and Couper, {David J} and Gabe Crawford and Doney, {Alex S F} and Elliott, {Katherine S} and Elliott, {Amanda L} and Erdos, {Michael R} and Niels Grarup and Torben J{\o}rgensen and Thomas Spars{\o} and Torben Hansen and Oluf Pedersen and {MAGIC investigators}",

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AU - Voight, Benjamin F

AU - Scott, Laura J

AU - Steinthorsdottir, Valgerdur

AU - Morris, Andrew P

AU - Dina, Christian

AU - Welch, Ryan P

AU - Zeggini, Eleftheria

AU - Huth, Cornelia

AU - Aulchenko, Yurii S

AU - Thorleifsson, Gudmar

AU - McCulloch, Laura J

AU - Ferreira, Teresa

AU - Grallert, Harald

AU - Amin, Najaf

AU - Wu, Guanming

AU - Willer, Cristen J

AU - Raychaudhuri, Soumya

AU - McCarroll, Steve A

AU - Langenberg, Claudia

AU - Hofmann, Oliver M

AU - Dupuis, Josée

AU - Qi, Lu

AU - Segrè, Ayellet V

AU - van Hoek, Mandy

AU - Navarro, Pau

AU - Ardlie, Kristin

AU - Balkau, Beverley

AU - Benediktsson, Rafn

AU - Bennett, Amanda J

AU - Blagieva, Roza

AU - Boerwinkle, Eric

AU - Bonnycastle, Lori L

AU - Bengtsson Boström, Kristina

AU - Bravenboer, Bert

AU - Bumpstead, Suzannah

AU - Burtt, Noisël P

AU - Charpentier, Guillaume

AU - Chines, Peter S

AU - Cornelis, Marilyn

AU - Couper, David J

AU - Crawford, Gabe

AU - Doney, Alex S F

AU - Elliott, Katherine S

AU - Elliott, Amanda L

AU - Erdos, Michael R

AU - Grarup, Niels

AU - Jørgensen, Torben

AU - Sparsø, Thomas

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - MAGIC investigators

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N2 - By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P 5 × 10 8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

AB - By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P 5 × 10 8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

KW - Blood Glucose

KW - Diabetes Mellitus, Type 2

KW - Dual-Specificity Phosphatases

KW - Fasting

KW - Gene Dosage

KW - Gene Expression Profiling

KW - Genetic Heterogeneity

KW - Genetic Predisposition to Disease

KW - Genome, Human

KW - Genome-Wide Association Study

KW - Hepatocyte Nuclear Factor 1-alpha

KW - Humans

KW - KCNQ1 Potassium Channel

KW - Meta-Analysis as Topic

KW - Mitogen-Activated Protein Kinase Phosphatases

KW - Polymorphism, Single Nucleotide

U2 - 10.1038/ng.609

DO - 10.1038/ng.609

M3 - Journal article

C2 - 20581827

SN - 1061-4036

VL - 42

SP - 579

EP - 589

JO - Nature: New biology

JF - Nature: New biology

IS - 7

ER -

Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

Abstract

Keywords

UN SDGs

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