Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms

T2D-GENES Consortium

doi:10.1093/hmg/ddw048

Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms

T2D-GENES Consortium

Department of Human Biology

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

Abstract

To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.

Original language	English
Pages (from-to)	2070-2081
Number of pages	12
Journal	Human Molecular Genetics
Volume	25
Issue number	10
DOIs	https://doi.org/10.1093/hmg/ddw048
State	Published - 15 May 2016

Bibliographical note

Funding Information:
L.P. is a recipient of a Ramon y Cajal contract from the Spanish Ministry of Economy and Competitiveness (RYC 2014-0069) and a Rising Star Award from the European Foundation for the Study of Diabetes (EFSD). J.C.F. is a Massachusetts General Hospital Research Scholar. N.K. is a recipient of the Okinga Scholarship, and thanks Dr Shoichi Okinaga, Dr Hiroko Okinaga and other staff at Teikyo University, Japan. M.I.M. is aWellcome Trust Senior Investigator and NIHR Senior Investigator. A.P.M. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science. The BBJ study thanks all the participants and the staff of the BioBank Japan project. The CAGE study thanks Dr Eitaro Nakashima, Dr Jiro Nakamura, Dr Mitsuhiro Yokota and Dr Masato Isono for their assistance in collecting the DNA samples and the accompanying clinical information, and genotyping. The DGDG study thanks C. Petit, J-P. Riveline and S. Franc for recruitment, and S. Brunet, F. Bacot, R. Frechette, V. Catudal, M. Deweirder, F. Allegaert, P. Laflamme, P. Lepage, W. Astle, M. Leboeuf and S. Leroux for technical assistance. The DGDG study also thanks K. Shazand and N. Foisset for organizational guidance, and thanks Rob Sladek for his contribution to the study design. The work for the LOLIPOP study was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The LOLIPOP study also thanks the participants and research staff who made the study possible. The LONGENITY study thanks Professor Aviv Bergman for providing genotypes. We thank Javier Garcia-Hurtado (IDIBAPS) and Helena Raurell (IGTP) for technical support.This workwas supported by Action on Hearing Loss (G51); American Federation for Aging; Einstein Glenn Center; Association Francaise des Diabetiques; British Heart Foundation (SP/04/002); CARDIOMED BSC0122(6)-CSIR, India; Centre Hospitalier Universitaire Poitiers; CNAMTS; Endocrinology-Diabetology Department of the Corbeil-Essonnes Hospital; European Union (FP7 EpiMigrant, 279143); Focused Investment Scheme of the Chinese University of Hong Kong; Fondation de France; Hong Kong Foundation for Research and Development in Diabetes; Genome Canada; Génome Quebec; Hong Kong Government Research Grant Committee Central Allocation Scheme (CUHK 1/04C), Innovation and Technology Fund (ITS/487/09FP and ITS/130/11), and the Research Grants Council Theme-based Research Scheme (T12-402/13N); Japan Society for the Promotion of Science (KAKENHI 23710228); Medical Research Council (G0601966, G0700931); Ministerio de Economía y Competitividad (BFU2014-58150-R); Ministry of Education, Culture, Sports, Science and Technology of Japan; National Center for Global Health and Medicine (NCGM); National Institute of Aging (PO1AG027734, R01AG046949, 1R01AG042188, P30AG038072, R014AG028872); National Institutes of Health (K24-DK080140, U01-DK085526, R01-MH101820, P60-DK20595, U01-DK085501, R01-HL102830, U01-HG005773, R01-MH090937, R01-HL102830, R01-HG000376, R01-DK062370, R01-DK073541, U01-DK085524, U01-DK085545, U01-DK085584, U01-DK105535); National Institute for Health Research (RP-PG-0407-10371); National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust; National Medical Research Program, Singapore; National Research Foundation of Korea (NRF-2012R1A2A1A03006155, 2012R1A3A2026438, 2013M3A9C4078158, 2015R1A5A6001906); Program for Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation Organization (NIBIO); Wellcome Trust (WT084723, WT090532, WT098017, WT098051). The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.

Publisher Copyright:
© The Author 2016. Published by Oxford University Press.

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

UN SDGs

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

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10.1093/hmg/ddw048

Cite this

@article{cff41e9cfad646109e0d649ade28ce79,

title = "Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms",

abstract = "To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.",

author = "{T2D-GENES Consortium} and Momoko Horikoshi and Lorenzo Pasquali and Steven Wiltshire and Huyghe, {Jeroen R.} and Anubha Mahajan and Asimit, {Jennifer L.} and Teresa Ferreira and Locke, {Adam E.} and Robertson, {Neil R.} and Xu Wang and Xueling Sim and Hayato Fujita and Kazuo Hara and Robin Young and Weihua Zhang and Sungkyoung Choi and Han Chen and Ismeet Kaur and Fumihiko Takeuchi and Pierre Fontanillas and Doroth{\'e}e Thuillier and Loic Yengo and Below, {Jennifer E.} and Tam, {Claudia H.T.} and Ying Wu and Gon{\c c}alo Abecasis and David Altshuler and Bell, {Graeme I.} and John Blangero and Burtt, {No{\'e}l P.} and Ravindranath Duggirala and Florez, {Jose C.} and Hanis, {Craig L.} and Mark Seielstad and Gil Atzmon and Chan, {Juliana C.N.} and Ma, {Ronald C.W.} and Philippe Froguel and Wilson, {James G.} and Dwaipayan Bharadwaj and Josee Dupuis and Meigs, {James B.} and Cho, {Yoon Shin} and Taesung Park and Kooner, {Jaspal S.} and Chambers, {John C.} and Danish Saleheen and Takashi Kadowaki and {Shyong Tai}, E. and Mohlke, {Karen L.}",

note = "Funding Information: L.P. is a recipient of a Ramon y Cajal contract from the Spanish Ministry of Economy and Competitiveness (RYC 2014-0069) and a Rising Star Award from the European Foundation for the Study of Diabetes (EFSD). J.C.F. is a Massachusetts General Hospital Research Scholar. N.K. is a recipient of the Okinga Scholarship, and thanks Dr Shoichi Okinaga, Dr Hiroko Okinaga and other staff at Teikyo University, Japan. M.I.M. is aWellcome Trust Senior Investigator and NIHR Senior Investigator. A.P.M. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science. The BBJ study thanks all the participants and the staff of the BioBank Japan project. The CAGE study thanks Dr Eitaro Nakashima, Dr Jiro Nakamura, Dr Mitsuhiro Yokota and Dr Masato Isono for their assistance in collecting the DNA samples and the accompanying clinical information, and genotyping. The DGDG study thanks C. Petit, J-P. Riveline and S. Franc for recruitment, and S. Brunet, F. Bacot, R. Frechette, V. Catudal, M. Deweirder, F. Allegaert, P. Laflamme, P. Lepage, W. Astle, M. Leboeuf and S. Leroux for technical assistance. The DGDG study also thanks K. Shazand and N. Foisset for organizational guidance, and thanks Rob Sladek for his contribution to the study design. The work for the LOLIPOP study was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The LOLIPOP study also thanks the participants and research staff who made the study possible. The LONGENITY study thanks Professor Aviv Bergman for providing genotypes. We thank Javier Garcia-Hurtado (IDIBAPS) and Helena Raurell (IGTP) for technical support.This workwas supported by Action on Hearing Loss (G51); American Federation for Aging; Einstein Glenn Center; Association Francaise des Diabetiques; British Heart Foundation (SP/04/002); CARDIOMED BSC0122(6)-CSIR, India; Centre Hospitalier Universitaire Poitiers; CNAMTS; Endocrinology-Diabetology Department of the Corbeil-Essonnes Hospital; European Union (FP7 EpiMigrant, 279143); Focused Investment Scheme of the Chinese University of Hong Kong; Fondation de France; Hong Kong Foundation for Research and Development in Diabetes; Genome Canada; G{\'e}nome Quebec; Hong Kong Government Research Grant Committee Central Allocation Scheme (CUHK 1/04C), Innovation and Technology Fund (ITS/487/09FP and ITS/130/11), and the Research Grants Council Theme-based Research Scheme (T12-402/13N); Japan Society for the Promotion of Science (KAKENHI 23710228); Medical Research Council (G0601966, G0700931); Ministerio de Econom{\'i}a y Competitividad (BFU2014-58150-R); Ministry of Education, Culture, Sports, Science and Technology of Japan; National Center for Global Health and Medicine (NCGM); National Institute of Aging (PO1AG027734, R01AG046949, 1R01AG042188, P30AG038072, R014AG028872); National Institutes of Health (K24-DK080140, U01-DK085526, R01-MH101820, P60-DK20595, U01-DK085501, R01-HL102830, U01-HG005773, R01-MH090937, R01-HL102830, R01-HG000376, R01-DK062370, R01-DK073541, U01-DK085524, U01-DK085545, U01-DK085584, U01-DK105535); National Institute for Health Research (RP-PG-0407-10371); National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust; National Medical Research Program, Singapore; National Research Foundation of Korea (NRF-2012R1A2A1A03006155, 2012R1A3A2026438, 2013M3A9C4078158, 2015R1A5A6001906); Program for Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation Organization (NIBIO); Wellcome Trust (WT084723, WT090532, WT098017, WT098051). The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. Publisher Copyright: {\textcopyright} The Author 2016. Published by Oxford University Press.",

year = "2016",

month = may,

day = "15",

doi = "10.1093/hmg/ddw048",

language = "English",

volume = "25",

pages = "2070--2081",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "10",

}

TY - JOUR

T1 - Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms

AU - T2D-GENES Consortium

AU - Horikoshi, Momoko

AU - Pasquali, Lorenzo

AU - Wiltshire, Steven

AU - Huyghe, Jeroen R.

AU - Mahajan, Anubha

AU - Asimit, Jennifer L.

AU - Ferreira, Teresa

AU - Locke, Adam E.

AU - Robertson, Neil R.

AU - Wang, Xu

AU - Sim, Xueling

AU - Fujita, Hayato

AU - Hara, Kazuo

AU - Young, Robin

AU - Zhang, Weihua

AU - Choi, Sungkyoung

AU - Chen, Han

AU - Kaur, Ismeet

AU - Takeuchi, Fumihiko

AU - Fontanillas, Pierre

AU - Thuillier, Dorothée

AU - Yengo, Loic

AU - Below, Jennifer E.

AU - Tam, Claudia H.T.

AU - Wu, Ying

AU - Abecasis, Gonçalo

AU - Altshuler, David

AU - Bell, Graeme I.

AU - Blangero, John

AU - Burtt, Noél P.

AU - Duggirala, Ravindranath

AU - Florez, Jose C.

AU - Hanis, Craig L.

AU - Seielstad, Mark

AU - Atzmon, Gil

AU - Chan, Juliana C.N.

AU - Ma, Ronald C.W.

AU - Froguel, Philippe

AU - Wilson, James G.

AU - Bharadwaj, Dwaipayan

AU - Dupuis, Josee

AU - Meigs, James B.

AU - Cho, Yoon Shin

AU - Park, Taesung

AU - Kooner, Jaspal S.

AU - Chambers, John C.

AU - Saleheen, Danish

AU - Kadowaki, Takashi

AU - Shyong Tai, E.

AU - Mohlke, Karen L.

N1 - Funding Information: L.P. is a recipient of a Ramon y Cajal contract from the Spanish Ministry of Economy and Competitiveness (RYC 2014-0069) and a Rising Star Award from the European Foundation for the Study of Diabetes (EFSD). J.C.F. is a Massachusetts General Hospital Research Scholar. N.K. is a recipient of the Okinga Scholarship, and thanks Dr Shoichi Okinaga, Dr Hiroko Okinaga and other staff at Teikyo University, Japan. M.I.M. is aWellcome Trust Senior Investigator and NIHR Senior Investigator. A.P.M. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science. The BBJ study thanks all the participants and the staff of the BioBank Japan project. The CAGE study thanks Dr Eitaro Nakashima, Dr Jiro Nakamura, Dr Mitsuhiro Yokota and Dr Masato Isono for their assistance in collecting the DNA samples and the accompanying clinical information, and genotyping. The DGDG study thanks C. Petit, J-P. Riveline and S. Franc for recruitment, and S. Brunet, F. Bacot, R. Frechette, V. Catudal, M. Deweirder, F. Allegaert, P. Laflamme, P. Lepage, W. Astle, M. Leboeuf and S. Leroux for technical assistance. The DGDG study also thanks K. Shazand and N. Foisset for organizational guidance, and thanks Rob Sladek for his contribution to the study design. The work for the LOLIPOP study was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The LOLIPOP study also thanks the participants and research staff who made the study possible. The LONGENITY study thanks Professor Aviv Bergman for providing genotypes. We thank Javier Garcia-Hurtado (IDIBAPS) and Helena Raurell (IGTP) for technical support.This workwas supported by Action on Hearing Loss (G51); American Federation for Aging; Einstein Glenn Center; Association Francaise des Diabetiques; British Heart Foundation (SP/04/002); CARDIOMED BSC0122(6)-CSIR, India; Centre Hospitalier Universitaire Poitiers; CNAMTS; Endocrinology-Diabetology Department of the Corbeil-Essonnes Hospital; European Union (FP7 EpiMigrant, 279143); Focused Investment Scheme of the Chinese University of Hong Kong; Fondation de France; Hong Kong Foundation for Research and Development in Diabetes; Genome Canada; Génome Quebec; Hong Kong Government Research Grant Committee Central Allocation Scheme (CUHK 1/04C), Innovation and Technology Fund (ITS/487/09FP and ITS/130/11), and the Research Grants Council Theme-based Research Scheme (T12-402/13N); Japan Society for the Promotion of Science (KAKENHI 23710228); Medical Research Council (G0601966, G0700931); Ministerio de Economía y Competitividad (BFU2014-58150-R); Ministry of Education, Culture, Sports, Science and Technology of Japan; National Center for Global Health and Medicine (NCGM); National Institute of Aging (PO1AG027734, R01AG046949, 1R01AG042188, P30AG038072, R014AG028872); National Institutes of Health (K24-DK080140, U01-DK085526, R01-MH101820, P60-DK20595, U01-DK085501, R01-HL102830, U01-HG005773, R01-MH090937, R01-HL102830, R01-HG000376, R01-DK062370, R01-DK073541, U01-DK085524, U01-DK085545, U01-DK085584, U01-DK105535); National Institute for Health Research (RP-PG-0407-10371); National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust; National Medical Research Program, Singapore; National Research Foundation of Korea (NRF-2012R1A2A1A03006155, 2012R1A3A2026438, 2013M3A9C4078158, 2015R1A5A6001906); Program for Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation Organization (NIBIO); Wellcome Trust (WT084723, WT090532, WT098017, WT098051). The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. Publisher Copyright: © The Author 2016. Published by Oxford University Press.

PY - 2016/5/15

Y1 - 2016/5/15

N2 - To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.

AB - To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.

UR - http://www.scopus.com/inward/record.url?scp=84992187678&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddw048

DO - 10.1093/hmg/ddw048

M3 - Article

C2 - 26911676

AN - SCOPUS:84992187678

SN - 0964-6906

VL - 25

SP - 2070

EP - 2081

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 10

ER -

Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms

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Bibliographical note

ASJC Scopus subject areas

UN SDGs

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