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; Peter Almgren; Ben F Voight; Harald Grallert; Martina Müller-Nurasyid; Janina S Ried; William N 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; Augustine Kong; Gunnar Sigurðsson; Nicola D Kerrison; Jian'an Luan; Liming Liang; Thomas Meitinger; Michael Roden; Barbara Thorand; Tõnu Esko; Evelin Mihailov; Caroline Fox; Ching-Ti Liu; Denis Rybin; Bo Isomaa; Valeriya Lyssenko; Tiinamaija Tuomi; David J Couper; James S Pankow; Niels Grarup; Christian T Have; Marit E Jørgensen; Torben Jørgensen; Allan Linneberg; Marilyn C Cornelis; Rob M van Dam; David J Hunter; Peter Kraft; Qi Sun; Sarah Edkins; Katharine R Owen; John Rb Perry; Andrew R Wood; Eleftheria Zeggini; Juan Tajes-Fernandes; Goncalo R Abecasis; Lori L Bonnycastle; Peter S Chines; Heather M Stringham; Heikki A Koistinen; Leena Kinnunen; Bengt Sennblad; Thomas W Mühleisen; Markus M Nöthen; Sonali Pechlivanis; Damiano Baldassarre; Karl Gertow; Steve E Humphries; Elena Tremoli; Norman Klopp; Julia Meyer; Gerald Steinbach; Roman Wennauer; Johan G Eriksson; Satu Mӓnnistö; Leena Peltonen; Emmi Tikkanen; Guillaume Charpentier; Elodie Eury; Stéphane Lobbens; Bruna Gigante; Karin Leander; Olga McLeod; Erwin P Bottinger; Omri Gottesman; Douglas Ruderfer; Matthias Blüher; Peter Kovacs; Anke Tonjes; Nisa M Maruthur; Chiara Scapoli; Raimund Erbel; Karl-Heinz Jöckel; Susanne Moebus; Ulf de Faire; Anders Hamsten; Michael Stumvoll; Panagiotis Deloukas; Peter J Donnelly; Timothy M Frayling; Andrew T Hattersley; Samuli Ripatti; Veikko Salomaa; Nancy L Pedersen; Bernhard O Boehm; Richard N Bergman; Francis S Collins; Karen L Mohlke; Jaakko Tuomilehto; Torben Hansen; Oluf Pedersen; Inês Barroso; Lars Lannfelt; Erik Ingelsson; Lars Lind; Cecilia M Lindgren; Stephane Cauchi; Philippe Froguel; Ruth Jf Loos; Beverley Balkau; Heiner Boeing; Paul W Franks; Aurelio Barricarte Gurrea; Domenico Palli; Yvonne T van der Schouw; David Altshuler; Leif C Groop; Claudia Langenberg; Nicholas J Wareham; Eric Sijbrands; Cornelia M van Duijn; Jose C Florez; James B Meigs; Eric Boerwinkle; Christian Gieger; Konstantin Strauch; Andres Metspalu; Andrew D Morris; Colin Na Palmer; Frank B Hu; Unnur Thorsteinsdottir; Kari Stefansson; Josée Dupuis; Andrew P Morris; Michael Boehnke; Mark I McCarthy; Inga Prokopenko

doi:10.2337/db16-1253

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 ChenPeter Almgren, Ben F Voight, Harald Grallert, Martina Müller-Nurasyid, Janina S Ried, William N 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, Augustine Kong, Gunnar Sigurðsson, Nicola D Kerrison, Jian'an Luan, Liming Liang, Thomas Meitinger, Michael Roden, Barbara Thorand, Tõnu Esko, Evelin Mihailov, Caroline Fox, Ching-Ti Liu, Denis Rybin, Bo Isomaa, Valeriya Lyssenko, Tiinamaija Tuomi, David J Couper, James S Pankow, Niels Grarup, Christian T Have, Marit E Jørgensen, Torben Jørgensen, Allan Linneberg, Marilyn C Cornelis, Rob M van Dam, David J Hunter, Peter Kraft, Qi Sun, Sarah Edkins, Katharine R Owen, John Rb Perry, Andrew R Wood, Eleftheria Zeggini, Juan Tajes-Fernandes, Goncalo R Abecasis, Lori L Bonnycastle, Peter S Chines, Heather M Stringham, Heikki A Koistinen, Leena Kinnunen, Bengt Sennblad, Thomas W Mühleisen, Markus M Nöthen, Sonali Pechlivanis, Damiano Baldassarre, Karl Gertow, Steve E Humphries, Elena Tremoli, Norman Klopp, Julia Meyer, Gerald Steinbach, Roman Wennauer, Johan G Eriksson, Satu Mӓnnistö, Leena Peltonen, Emmi Tikkanen, Guillaume Charpentier, Elodie Eury, Stéphane Lobbens, Bruna Gigante, Karin Leander, Olga McLeod, Erwin P Bottinger, Omri Gottesman, Douglas Ruderfer, Matthias Blüher, Peter Kovacs, Anke Tonjes, Nisa M Maruthur, Chiara Scapoli, Raimund Erbel, Karl-Heinz Jöckel, Susanne Moebus, Ulf de Faire, Anders Hamsten, Michael Stumvoll, Panagiotis Deloukas, Peter J Donnelly, Timothy M Frayling, Andrew T Hattersley, Samuli Ripatti, Veikko Salomaa, Nancy L Pedersen, Bernhard O Boehm, Richard N Bergman, Francis S Collins, Karen L Mohlke, Jaakko Tuomilehto, Torben Hansen, Oluf Pedersen, Inês Barroso, Lars Lannfelt, Erik Ingelsson, Lars Lind, Cecilia M Lindgren, Stephane Cauchi, Philippe Froguel, Ruth Jf Loos, Beverley Balkau, Heiner Boeing, Paul W Franks, Aurelio Barricarte Gurrea, Domenico Palli, Yvonne T van der Schouw, David Altshuler, Leif C Groop, Claudia Langenberg, Nicholas J Wareham, Eric Sijbrands, Cornelia M van Duijn, Jose C Florez, James B Meigs, Eric Boerwinkle, Christian Gieger, Konstantin Strauch, Andres Metspalu, Andrew D Morris, Colin Na Palmer, Frank B Hu, Unnur Thorsteinsdottir, Kari Stefansson, Josée Dupuis, Andrew P Morris, Michael Boehnke, Mark I McCarthy, Inga Prokopenko

274 Citations (Scopus)

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 language	English
Journal	Diabetes
Volume	66
Issue number	11
Pages (from-to)	2888-2902
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db16-1253
Publication status	Published - 1 Nov 2017

Keywords

Journal Article

UN SDGs

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

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Scott, R. A., Scott, L. J., Mägi, R., Marullo, L., Gaulton, K. J., Kaakinen, M., Pervjakova, N., Pers, T. H., Johnson, A. D., Eicher, J. D., Jackson, A. U., Ferreira, T., Lee, Y., Ma, C., Steinthorsdottir, V., Thorleifsson, G., Qi, L., Van Zuydam, N. R., Mahajan, A., ... Prokopenko, I. (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

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, WN, 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, Kong, A, Sigurðsson, G, Kerrison, ND, Luan, J, Liang, L, Meitinger, T, Roden, M, Thorand, B, Esko, T, Mihailov, E, Fox, C, Liu, C-T, Rybin, D, Isomaa, B, Lyssenko, V, Tuomi, T, Couper, DJ, Pankow, JS, Grarup, N, Have, CT, Jørgensen, ME, Jørgensen, T, Linneberg, A, Cornelis, MC, van Dam, RM, Hunter, DJ, Kraft, P, Sun, Q, Edkins, S, Owen, KR, Perry, JR, Wood, AR, Zeggini, E, Tajes-Fernandes, J, Abecasis, GR, Bonnycastle, LL, Chines, PS, Stringham, HM, Koistinen, HA, Kinnunen, L, Sennblad, B, Mühleisen, TW, Nöthen, MM, Pechlivanis, S, Baldassarre, D, Gertow, K, Humphries, SE, Tremoli, E, Klopp, N, Meyer, J, Steinbach, G, Wennauer, R, Eriksson, JG, Mӓnnistö, S, Peltonen, L, Tikkanen, E, Charpentier, G, Eury, E, Lobbens, S, Gigante, B, Leander, K, McLeod, O, Bottinger, EP, Gottesman, O, Ruderfer, D, Blüher, M, Kovacs, P, Tonjes, A, Maruthur, NM, Scapoli, C, Erbel, R, Jöckel, K-H, Moebus, S, de Faire, U, Hamsten, A, Stumvoll, M, Deloukas, P, Donnelly, PJ, Frayling, TM, Hattersley, AT, Ripatti, S, Salomaa, V, Pedersen, NL, Boehm, BO, Bergman, RN, Collins, FS, Mohlke, KL, Tuomilehto, J, Hansen, T , Pedersen, O, Barroso, I, Lannfelt, L, Ingelsson, E, Lind, L, Lindgren, CM, Cauchi, S, Froguel, P, Loos, RJ, Balkau, B, Boeing, H, Franks, PW, Gurrea, AB, Palli, D, van der Schouw, YT, Altshuler, D, Groop, LC, Langenberg, C, Wareham, NJ, Sijbrands, E, van Duijn, CM, Florez, JC, Meigs, JB, Boerwinkle, E, Gieger, C, Strauch, K, Metspalu, A, Morris, AD, Palmer, CN, Hu, FB, Thorsteinsdottir, U, Stefansson, K, Dupuis, J, Morris, AP, Boehnke, M, McCarthy, MI & Prokopenko, I 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

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title = "An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans",

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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note = "{\textcopyright} 2017 by the American Diabetes Association.",

year = "2017",

month = nov,

day = "1",

doi = "10.2337/db16-1253",

language = "English",

volume = "66",

pages = "2888--2902",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "11",

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TY - JOUR

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, William N

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 - Kong, Augustine

AU - Sigurðsson, Gunnar

AU - Kerrison, Nicola D

AU - Luan, Jian'an

AU - Liang, Liming

AU - Meitinger, Thomas

AU - Roden, Michael

AU - Thorand, Barbara

AU - Esko, Tõnu

AU - Mihailov, Evelin

AU - Fox, Caroline

AU - Liu, Ching-Ti

AU - Rybin, Denis

AU - Isomaa, Bo

AU - Lyssenko, Valeriya

AU - Tuomi, Tiinamaija

AU - Couper, David J

AU - Pankow, James S

AU - Grarup, Niels

AU - Have, Christian T

AU - Jørgensen, Marit E

AU - Jørgensen, Torben

AU - Linneberg, Allan

AU - Cornelis, Marilyn C

AU - van Dam, Rob M

AU - Hunter, David J

AU - Kraft, Peter

AU - Sun, Qi

AU - Edkins, Sarah

AU - Owen, Katharine R

AU - Perry, John Rb

AU - Wood, Andrew R

AU - Zeggini, Eleftheria

AU - Tajes-Fernandes, Juan

AU - Abecasis, Goncalo R

AU - Bonnycastle, Lori L

AU - Chines, Peter S

AU - Stringham, Heather M

AU - Koistinen, Heikki A

AU - Kinnunen, Leena

AU - Sennblad, Bengt

AU - Mühleisen, Thomas W

AU - Nöthen, Markus M

AU - Pechlivanis, Sonali

AU - Baldassarre, Damiano

AU - Gertow, Karl

AU - Humphries, Steve E

AU - Tremoli, Elena

AU - Klopp, Norman

AU - Meyer, Julia

AU - Steinbach, Gerald

AU - Wennauer, Roman

AU - Eriksson, Johan G

AU - Mӓnnistö, Satu

AU - Peltonen, Leena

AU - Tikkanen, Emmi

AU - Charpentier, Guillaume

AU - Eury, Elodie

AU - Lobbens, Stéphane

AU - Gigante, Bruna

AU - Leander, Karin

AU - McLeod, Olga

AU - Bottinger, Erwin P

AU - Gottesman, Omri

AU - Ruderfer, Douglas

AU - Blüher, Matthias

AU - Kovacs, Peter

AU - Tonjes, Anke

AU - Maruthur, Nisa M

AU - Scapoli, Chiara

AU - Erbel, Raimund

AU - Jöckel, Karl-Heinz

AU - Moebus, Susanne

AU - de Faire, Ulf

AU - Hamsten, Anders

AU - Stumvoll, Michael

AU - Deloukas, Panagiotis

AU - Donnelly, Peter J

AU - Frayling, Timothy M

AU - Hattersley, Andrew T

AU - Ripatti, Samuli

AU - Salomaa, Veikko

AU - Pedersen, Nancy L

AU - Boehm, Bernhard O

AU - Bergman, Richard N

AU - Collins, Francis S

AU - Mohlke, Karen L

AU - Tuomilehto, Jaakko

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Barroso, Inês

AU - Lannfelt, Lars

AU - Ingelsson, Erik

AU - Lind, Lars

AU - Lindgren, Cecilia M

AU - Cauchi, Stephane

AU - Froguel, Philippe

AU - Loos, Ruth Jf

AU - Balkau, Beverley

AU - Boeing, Heiner

AU - Franks, Paul W

AU - Gurrea, Aurelio Barricarte

AU - Palli, Domenico

AU - van der Schouw, Yvonne T

AU - Altshuler, David

AU - Groop, Leif C

AU - Langenberg, Claudia

AU - Wareham, Nicholas J

AU - Sijbrands, Eric

AU - van Duijn, Cornelia M

AU - Florez, Jose C

AU - Meigs, James B

AU - Boerwinkle, Eric

AU - Gieger, Christian

AU - Strauch, Konstantin

AU - Metspalu, Andres

AU - Morris, Andrew D

AU - Palmer, Colin Na

AU - Hu, Frank B

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

AU - Dupuis, Josée

AU - Morris, Andrew P

AU - Boehnke, Michael

AU - McCarthy, Mark I

AU - Prokopenko, Inga

PY - 2017/11/1

Y1 - 2017/11/1

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.

AB - 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.

KW - Journal Article

U2 - 10.2337/db16-1253

DO - 10.2337/db16-1253

M3 - Journal article

C2 - 28566273

SN - 0012-1797

VL - 66

SP - 2888

EP - 2902

JO - Diabetes

JF - Diabetes

IS - 11

ER -

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

Abstract

Keywords

UN SDGs

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