Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease

CHD Exome+ Consortium; EPIC-InterAct Consortium; Michigan Biobank; Wei Zhao; Asif Rasheed; Emmi Tikkanen; Jung-Jin Lee; Adam S. Butterworth; Joanna M. M. Howson; Themistocles L. Assimes; Rajiv Chowdhury; Marju Orho-Melander; Scott Damrauer; Aeron Small; Senay Asma; Minako Imamura; Toshimasa Yamauch; John C. Chambers; Peng Chen; Bishwa R. Sapkota; Nabi Shah; Sehrish Jabeen; Praveen Surendran; Yingchang Lu; Weihua Zhang; Atif Imran; Shahid Abbas; Faisal Majeed; Kevin Trindade; Nadeem Qamar; Nadeem Hayyat Mallick; Zia Yaqoob; Tahir Saghir; Syed Nadeem Hasan Rizvi; Anis Memon; Syed Zahed Rasheed; Fazal-Ur-Rehman Memon; Khalid Mehmood; Naveeduddin Ahmed; Irshad Hussain Qureshi; null Tanveer-Us-Salam; Wasim Iqbal; Uzma Malik; Narinder Mehra; Jane Z. Kuo; Wayne H-H Sheu; Xiuqing Guo; Chao A. Hsiung; Jyh-Ming J Juang; Kent D. Taylor; Yi-Jen Hung; Wen-Jane Lee; Thomas Quertermous; I.-Te Lee; Chih-Cheng Hsu; Erwin P. Bottinger; Sarju Ralhan; Yik-Ying Teo; Tzung-Dau Wang; Dewan S. Alam; Emanuele Di Angelantonio; Steve Epstein; Sune F. Nielsen; Børge G. Nordestgaard; Anne Tybjærg-Hansen; Robin Young; Marianne Benn; Ruth Frikke-Schmidt; Pia R. Kamstrup; J. Wouter Jukema; Naveed Sattar; Roelof A. J. Smit; Ren-Hua Chung; Kae-Woei Liang; Sonia S. Anand; Dharambir K. Sanghera; Samuli Ripatti; Ruth J. F. Loos; Jaspal S. Kooner; E. Shyong  Tai; Jerome I. Rotter; Yii-Der Ida Chen; Philippe Frossard; Shiro Maeda; Takashi Kadowaki; Muredach P. Reilly; Guillaume  Paré; Olle Melander; Veikko Salomaa; Daniel J. Rader; John Danesh; Benjamin F. Voight; Danish Saleheen

doi:10.1038/ng.3943

Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease

CHD Exome+ Consortium, EPIC-InterAct Consortium, Michigan Biobank, Wei Zhao, Asif Rasheed, Emmi Tikkanen, Jung-Jin Lee, Adam S. Butterworth, Joanna M. M. Howson, Themistocles L. Assimes, Rajiv Chowdhury, Marju Orho-Melander, Scott Damrauer, Aeron Small, Senay Asma, Minako Imamura, Toshimasa Yamauch, John C. Chambers, Peng Chen, Bishwa R. SapkotaNabi Shah, Sehrish Jabeen, Praveen Surendran, Yingchang Lu, Weihua Zhang, Atif Imran, Shahid Abbas, Faisal Majeed, Kevin Trindade, Nadeem Qamar, Nadeem Hayyat Mallick, Zia Yaqoob, Tahir Saghir, Syed Nadeem Hasan Rizvi, Anis Memon, Syed Zahed Rasheed, Fazal-Ur-Rehman Memon, Khalid Mehmood, Naveeduddin Ahmed, Irshad Hussain Qureshi, Tanveer-Us-Salam, Wasim Iqbal, Uzma Malik, Narinder Mehra, Jane Z. Kuo, Wayne H-H Sheu, Xiuqing Guo, Chao A. Hsiung, Jyh-Ming J Juang, Kent D. Taylor, Yi-Jen Hung, Wen-Jane Lee, Thomas Quertermous, I.-Te Lee, Chih-Cheng Hsu, Erwin P. Bottinger, Sarju Ralhan, Yik-Ying Teo, Tzung-Dau Wang, Dewan S. Alam, Emanuele Di Angelantonio, Steve Epstein, Sune F. Nielsen, Børge G. Nordestgaard, Anne Tybjærg-Hansen, Robin Young, Marianne Benn, Ruth Frikke-Schmidt, Pia R. Kamstrup, J. Wouter Jukema, Naveed Sattar, Roelof A. J. Smit, Ren-Hua Chung, Kae-Woei Liang, Sonia S. Anand, Dharambir K. Sanghera, Samuli Ripatti, Ruth J. F. Loos, Jaspal S. Kooner, E. Shyong Tai, Jerome I. Rotter, Yii-Der Ida Chen, Philippe Frossard, Shiro Maeda, Takashi Kadowaki, Muredach P. Reilly, Guillaume Paré, Olle Melander, Veikko Salomaa, Daniel J. Rader, John Danesh, Benjamin F. Voight (Lead / Corresponding author), Danish Saleheen (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

186 Citations (Scopus)

Abstract

To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.

Original language	English
Pages (from-to)	1450-1457
Number of pages	8
Journal	Nature Genetics
Volume	49
Issue number	10
Early online date	4 Sept 2017
DOIs	https://doi.org/10.1038/ng.3943
Publication status	Published - 2017

Keywords

Asia/epidemiology
Asian Continental Ancestry Group/genetics
Biomarkers
Comorbidity
Coronary Disease/epidemiology
Diabetes Mellitus, Type 2/drug therapy
Europe/epidemiology
European Continental Ancestry Group/genetics
Genetic Loci/genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
HLA-DRB5 Chains/genetics
Humans
Metabolic Networks and Pathways/genetics
Metabolic Syndrome/epidemiology
Molecular Targeted Therapy
Mutation, Missense
Polymorphism, Single Nucleotide
Risk Factors

UN SDGs

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

Access to Document

10.1038/ng.3943

Cite this

CHD Exome+ Consortium, EPIC-InterAct Consortium, Michigan Biobank, Zhao, W., Rasheed, A., Tikkanen, E., Lee, J.-J., Butterworth, A. S., Howson, J. M. M., Assimes, T. L., Chowdhury, R., Orho-Melander, M., Damrauer, S., Small, A., Asma, S., Imamura, M., Yamauch, T., Chambers, J. C., Chen, P., ... Saleheen, D. (2017). Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease. Nature Genetics, 49(10), 1450-1457. https://doi.org/10.1038/ng.3943

@article{fa6febbcc7e4449c9c08f56688df8fd6,

title = "Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease",

abstract = "To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.",

keywords = "Asia/epidemiology, Asian Continental Ancestry Group/genetics, Biomarkers, Comorbidity, Coronary Disease/epidemiology, Diabetes Mellitus, Type 2/drug therapy, Europe/epidemiology, European Continental Ancestry Group/genetics, Genetic Loci/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-DRB5 Chains/genetics, Humans, Metabolic Networks and Pathways/genetics, Metabolic Syndrome/epidemiology, Molecular Targeted Therapy, Mutation, Missense, Polymorphism, Single Nucleotide, Risk Factors",

author = "{CHD Exome+ Consortium} and {EPIC-InterAct Consortium} and {Michigan Biobank} and Wei Zhao and Asif Rasheed and Emmi Tikkanen and Jung-Jin Lee and Butterworth, {Adam S.} and Howson, {Joanna M. M.} and Assimes, {Themistocles L.} and Rajiv Chowdhury and Marju Orho-Melander and Scott Damrauer and Aeron Small and Senay Asma and Minako Imamura and Toshimasa Yamauch and Chambers, {John C.} and Peng Chen and Sapkota, {Bishwa R.} and Nabi Shah and Sehrish Jabeen and Praveen Surendran and Yingchang Lu and Weihua Zhang and Atif Imran and Shahid Abbas and Faisal Majeed and Kevin Trindade and Nadeem Qamar and Mallick, {Nadeem Hayyat} and Zia Yaqoob and Tahir Saghir and Rizvi, {Syed Nadeem Hasan} and Anis Memon and Rasheed, {Syed Zahed} and Fazal-Ur-Rehman Memon and Khalid Mehmood and Naveeduddin Ahmed and Qureshi, {Irshad Hussain} and Tanveer-Us-Salam and Wasim Iqbal and Uzma Malik and Narinder Mehra and Kuo, {Jane Z.} and Sheu, {Wayne H-H} and Xiuqing Guo and Hsiung, {Chao A.} and Juang, {Jyh-Ming J} and Taylor, {Kent D.} and Yi-Jen Hung and Wen-Jane Lee and Thomas Quertermous and I.-Te Lee and Chih-Cheng Hsu and Bottinger, {Erwin P.} and Sarju Ralhan and Yik-Ying Teo and Tzung-Dau Wang and Alam, {Dewan S.} and {Di Angelantonio}, Emanuele and Steve Epstein and Nielsen, {Sune F.} and Nordestgaard, {B{\o}rge G.} and Anne Tybj{\ae}rg-Hansen and Robin Young and Marianne Benn and Ruth Frikke-Schmidt and Kamstrup, {Pia R.} and Jukema, {J. Wouter} and Naveed Sattar and Smit, {Roelof A. J.} and Ren-Hua Chung and Kae-Woei Liang and Anand, {Sonia S.} and Sanghera, {Dharambir K.} and Samuli Ripatti and Loos, {Ruth J. F.} and Kooner, {Jaspal S.} and Tai, {E. Shyong} and Rotter, {Jerome I.} and Chen, {Yii-Der Ida} and Philippe Frossard and Shiro Maeda and Takashi Kadowaki and Reilly, {Muredach P.} and Guillaume Par{\'e} and Olle Melander and Veikko Salomaa and Rader, {Daniel J.} and John Danesh and Voight, {Benjamin F.} and Danish Saleheen",

year = "2017",

doi = "10.1038/ng.3943",

language = "English",

volume = "49",

pages = "1450--1457",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

}

CHD Exome+ Consortium, EPIC-InterAct Consortium, Michigan Biobank, Zhao, W, Rasheed, A, Tikkanen, E, Lee, J-J, Butterworth, AS, Howson, JMM, Assimes, TL, Chowdhury, R, Orho-Melander, M, Damrauer, S, Small, A, Asma, S, Imamura, M, Yamauch, T, Chambers, JC, Chen, P, Sapkota, BR, Shah, N, Jabeen, S, Surendran, P, Lu, Y, Zhang, W, Imran, A, Abbas, S, Majeed, F, Trindade, K, Qamar, N, Mallick, NH, Yaqoob, Z, Saghir, T, Rizvi, SNH, Memon, A, Rasheed, SZ, Memon, F-U-R, Mehmood, K, Ahmed, N, Qureshi, IH, Tanveer-Us-Salam, Iqbal, W, Malik, U, Mehra, N, Kuo, JZ, Sheu, WH-H, Guo, X, Hsiung, CA, Juang, J-MJ, Taylor, KD, Hung, Y-J, Lee, W-J, Quertermous, T, Lee, I-T, Hsu, C-C, Bottinger, EP, Ralhan, S, Teo, Y-Y, Wang, T-D, Alam, DS, Di Angelantonio, E, Epstein, S, Nielsen, SF, Nordestgaard, BG, Tybjærg-Hansen, A, Young, R, Benn, M, Frikke-Schmidt, R, Kamstrup, PR, Jukema, JW, Sattar, N, Smit, RAJ, Chung, R-H, Liang, K-W, Anand, SS, Sanghera, DK, Ripatti, S, Loos, RJF, Kooner, JS, Tai, ES, Rotter, JI, Chen, Y-DI, Frossard, P, Maeda, S, Kadowaki, T, Reilly, MP, Paré, G, Melander, O, Salomaa, V, Rader, DJ, Danesh, J, Voight, BF & Saleheen, D 2017, 'Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease', Nature Genetics, vol. 49, no. 10, pp. 1450-1457. https://doi.org/10.1038/ng.3943

TY - JOUR

T1 - Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease

AU - CHD Exome+ Consortium

AU - EPIC-InterAct Consortium

AU - Michigan Biobank

AU - Zhao, Wei

AU - Rasheed, Asif

AU - Tikkanen, Emmi

AU - Lee, Jung-Jin

AU - Butterworth, Adam S.

AU - Howson, Joanna M. M.

AU - Assimes, Themistocles L.

AU - Chowdhury, Rajiv

AU - Orho-Melander, Marju

AU - Damrauer, Scott

AU - Small, Aeron

AU - Asma, Senay

AU - Imamura, Minako

AU - Yamauch, Toshimasa

AU - Chambers, John C.

AU - Chen, Peng

AU - Sapkota, Bishwa R.

AU - Shah, Nabi

AU - Jabeen, Sehrish

AU - Surendran, Praveen

AU - Lu, Yingchang

AU - Zhang, Weihua

AU - Imran, Atif

AU - Abbas, Shahid

AU - Majeed, Faisal

AU - Trindade, Kevin

AU - Qamar, Nadeem

AU - Mallick, Nadeem Hayyat

AU - Yaqoob, Zia

AU - Saghir, Tahir

AU - Rizvi, Syed Nadeem Hasan

AU - Memon, Anis

AU - Rasheed, Syed Zahed

AU - Memon, Fazal-Ur-Rehman

AU - Mehmood, Khalid

AU - Ahmed, Naveeduddin

AU - Qureshi, Irshad Hussain

AU - Tanveer-Us-Salam, null

AU - Iqbal, Wasim

AU - Malik, Uzma

AU - Mehra, Narinder

AU - Kuo, Jane Z.

AU - Sheu, Wayne H-H

AU - Guo, Xiuqing

AU - Hsiung, Chao A.

AU - Juang, Jyh-Ming J

AU - Taylor, Kent D.

AU - Hung, Yi-Jen

AU - Lee, Wen-Jane

AU - Quertermous, Thomas

AU - Lee, I.-Te

AU - Hsu, Chih-Cheng

AU - Bottinger, Erwin P.

AU - Ralhan, Sarju

AU - Teo, Yik-Ying

AU - Wang, Tzung-Dau

AU - Alam, Dewan S.

AU - Di Angelantonio, Emanuele

AU - Epstein, Steve

AU - Nielsen, Sune F.

AU - Nordestgaard, Børge G.

AU - Tybjærg-Hansen, Anne

AU - Young, Robin

AU - Benn, Marianne

AU - Frikke-Schmidt, Ruth

AU - Kamstrup, Pia R.

AU - Jukema, J. Wouter

AU - Sattar, Naveed

AU - Smit, Roelof A. J.

AU - Chung, Ren-Hua

AU - Liang, Kae-Woei

AU - Anand, Sonia S.

AU - Sanghera, Dharambir K.

AU - Ripatti, Samuli

AU - Loos, Ruth J. F.

AU - Kooner, Jaspal S.

AU - Tai, E. Shyong

AU - Rotter, Jerome I.

AU - Chen, Yii-Der Ida

AU - Frossard, Philippe

AU - Maeda, Shiro

AU - Kadowaki, Takashi

AU - Reilly, Muredach P.

AU - Paré, Guillaume

AU - Melander, Olle

AU - Salomaa, Veikko

AU - Rader, Daniel J.

AU - Danesh, John

AU - Voight, Benjamin F.

AU - Saleheen, Danish

PY - 2017

Y1 - 2017

N2 - To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.

AB - To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.

KW - Asia/epidemiology

KW - Asian Continental Ancestry Group/genetics

KW - Biomarkers

KW - Comorbidity

KW - Coronary Disease/epidemiology

KW - Diabetes Mellitus, Type 2/drug therapy

KW - Europe/epidemiology

KW - European Continental Ancestry Group/genetics

KW - Genetic Loci/genetics

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - HLA-DRB5 Chains/genetics

KW - Humans

KW - Metabolic Networks and Pathways/genetics

KW - Metabolic Syndrome/epidemiology

KW - Molecular Targeted Therapy

KW - Mutation, Missense

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

U2 - 10.1038/ng.3943

DO - 10.1038/ng.3943

M3 - Article

C2 - 28869590

SN - 1061-4036

VL - 49

SP - 1450

EP - 1457

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease

Abstract

Keywords

UN SDGs

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