An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Robert A. Scott, Laura J. Scott, Reedik Mägi, Letizia Marullo, Kyle J. Gaulton, Marika Kaakinen, Natalia Pervjakova, Tune H. Pers, Andrew D. Johnson, John D. Eicher, Anne U. Jackson, Teresa Ferreira, Yeji Lee, Clement Ma, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Lu Qi, Natalie R. Van Zuydam, Anubha Mahajan, Han Chen & 31 others Peter Almgren, Ben F. Voight, Harald Grallert, Martina Müller-Nurasyid, Janina S. Ried, Nigel W. Rayner, Neil Robertson, Lennart C. Karssen, Elisabeth M. van Leeuwen, Sara M. Willems, Christian Fuchsberger, Phoenix Kwan, Tanya M. Teslovich, Pritam Chanda, Man Li, Yingchang Lu, Christian Dina, Dorothee Thuillier, Loic Yengo, Longda Jiang, Thomas Sparso, Hans A. Kestler, Himanshu Chheda, Lewin Eisele, Stefan Gustafsson, Mattias Frånberg, Rona J. Strawbridge, Rafn Benediktsson, Astradur B. Hreidarsson, James S. Pankow, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium

Research output: Contribution to journalArticle

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Abstract

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

Original languageEnglish (US)
Pages (from-to)2888-2902
Number of pages15
JournalDiabetes
Volume66
Issue number11
DOIs
StatePublished - Nov 1 2017

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Genome-Wide Association Study
Type 2 Diabetes Mellitus
Genome
Insulin
Biodiversity
Islets of Langerhans
Adipocytes
Gene Frequency
Sample Size
Haplotypes
Meta-Analysis
Monocytes
Hepatocytes
Nucleotides
Genes

Cite this

Scott, R. A., Scott, L. J., Mägi, R., Marullo, L., Gaulton, K. J., Kaakinen, M., ... DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium (2017). An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. Diabetes, 66(11), 2888-2902. https://doi.org/10.2337/db16-1253

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. / Scott, Robert A.; Scott, Laura J.; Mägi, Reedik; Marullo, Letizia; Gaulton, Kyle J.; Kaakinen, Marika; Pervjakova, Natalia; Pers, Tune H.; Johnson, Andrew D.; Eicher, John D.; Jackson, Anne U.; Ferreira, Teresa; Lee, Yeji; Ma, Clement; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Qi, Lu; Van Zuydam, Natalie R.; Mahajan, Anubha; Chen, Han; Almgren, Peter; Voight, Ben F.; Grallert, Harald; Müller-Nurasyid, Martina; Ried, Janina S.; Rayner, Nigel W.; Robertson, Neil; Karssen, Lennart C.; van Leeuwen, Elisabeth M.; Willems, Sara M.; Fuchsberger, Christian; Kwan, Phoenix; Teslovich, Tanya M.; Chanda, Pritam; Li, Man; Lu, Yingchang; Dina, Christian; Thuillier, Dorothee; Yengo, Loic; Jiang, Longda; Sparso, Thomas; Kestler, Hans A.; Chheda, Himanshu; Eisele, Lewin; Gustafsson, Stefan; Frånberg, Mattias; Strawbridge, Rona J.; Benediktsson, Rafn; Hreidarsson, Astradur B.; Pankow, James S.; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium.

In: Diabetes, Vol. 66, No. 11, 01.11.2017, p. 2888-2902.

Research output: Contribution to journalArticle

Scott, RA, Scott, LJ, Mägi, R, Marullo, L, Gaulton, KJ, Kaakinen, M, Pervjakova, N, Pers, TH, Johnson, AD, Eicher, JD, Jackson, AU, Ferreira, T, Lee, Y, Ma, C, Steinthorsdottir, V, Thorleifsson, G, Qi, L, Van Zuydam, NR, Mahajan, A, Chen, H, Almgren, P, Voight, BF, Grallert, H, Müller-Nurasyid, M, Ried, JS, Rayner, NW, Robertson, N, Karssen, LC, van Leeuwen, EM, Willems, SM, Fuchsberger, C, Kwan, P, Teslovich, TM, Chanda, P, Li, M, Lu, Y, Dina, C, Thuillier, D, Yengo, L, Jiang, L, Sparso, T, Kestler, HA, Chheda, H, Eisele, L, Gustafsson, S, Frånberg, M, Strawbridge, RJ, Benediktsson, R, Hreidarsson, AB, Pankow, JS & DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium 2017, 'An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans', Diabetes, vol. 66, no. 11, pp. 2888-2902. https://doi.org/10.2337/db16-1253
Scott RA, Scott LJ, Mägi R, Marullo L, Gaulton KJ, Kaakinen M et al. An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. Diabetes. 2017 Nov 1;66(11):2888-2902. https://doi.org/10.2337/db16-1253
Scott, Robert A. ; Scott, Laura J. ; Mägi, Reedik ; Marullo, Letizia ; Gaulton, Kyle J. ; Kaakinen, Marika ; Pervjakova, Natalia ; Pers, Tune H. ; Johnson, Andrew D. ; Eicher, John D. ; Jackson, Anne U. ; Ferreira, Teresa ; Lee, Yeji ; Ma, Clement ; Steinthorsdottir, Valgerdur ; Thorleifsson, Gudmar ; Qi, Lu ; Van Zuydam, Natalie R. ; Mahajan, Anubha ; Chen, Han ; Almgren, Peter ; Voight, Ben F. ; Grallert, Harald ; Müller-Nurasyid, Martina ; Ried, Janina S. ; Rayner, Nigel W. ; Robertson, Neil ; Karssen, Lennart C. ; van Leeuwen, Elisabeth M. ; Willems, Sara M. ; Fuchsberger, Christian ; Kwan, Phoenix ; Teslovich, Tanya M. ; Chanda, Pritam ; Li, Man ; Lu, Yingchang ; Dina, Christian ; Thuillier, Dorothee ; Yengo, Loic ; Jiang, Longda ; Sparso, Thomas ; Kestler, Hans A. ; Chheda, Himanshu ; Eisele, Lewin ; Gustafsson, Stefan ; Frånberg, Mattias ; Strawbridge, Rona J. ; Benediktsson, Rafn ; Hreidarsson, Astradur B. ; Pankow, James S. ; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium. / An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. In: Diabetes. 2017 ; Vol. 66, No. 11. pp. 2888-2902.
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abstract = "To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.",
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T1 - An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

AU - Scott, Robert A.

AU - Scott, Laura J.

AU - Mägi, Reedik

AU - Marullo, Letizia

AU - Gaulton, Kyle J.

AU - Kaakinen, Marika

AU - Pervjakova, Natalia

AU - Pers, Tune H.

AU - Johnson, Andrew D.

AU - Eicher, John D.

AU - Jackson, Anne U.

AU - Ferreira, Teresa

AU - Lee, Yeji

AU - Ma, Clement

AU - Steinthorsdottir, Valgerdur

AU - Thorleifsson, Gudmar

AU - Qi, Lu

AU - Van Zuydam, Natalie R.

AU - Mahajan, Anubha

AU - Chen, Han

AU - Almgren, Peter

AU - Voight, Ben F.

AU - Grallert, Harald

AU - Müller-Nurasyid, Martina

AU - Ried, Janina S.

AU - Rayner, Nigel W.

AU - Robertson, Neil

AU - Karssen, Lennart C.

AU - van Leeuwen, Elisabeth M.

AU - Willems, Sara M.

AU - Fuchsberger, Christian

AU - Kwan, Phoenix

AU - Teslovich, Tanya M.

AU - Chanda, Pritam

AU - Li, Man

AU - Lu, Yingchang

AU - Dina, Christian

AU - Thuillier, Dorothee

AU - Yengo, Loic

AU - Jiang, Longda

AU - Sparso, Thomas

AU - Kestler, Hans A.

AU - Chheda, Himanshu

AU - Eisele, Lewin

AU - Gustafsson, Stefan

AU - Frånberg, Mattias

AU - Strawbridge, Rona J.

AU - Benediktsson, Rafn

AU - Hreidarsson, Astradur B.

AU - Pankow, James S.

AU - DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium

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N2 - To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

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