Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin

Ching Ti Liu; Sridharan Raghavan; Nisa Maruthur; Edmond Kato Kabagambe; Jaeyoung Hong; Maggie C.Y. Ng; Marie France Hivert; Yingchang Lu; Ping An; Amy R. Bentley; Anne M. Drolet; Kyle J. Gaulton; Xiuqing Guo; Loren L. Armstrong; Marguerite R. Irvin; Man Li; Leonard Lipovich; Denis V. Rybin; Kent D. Taylor; Charles Agyemang; Nicholette D. Palmer; Brian E. Cade; Wei Min Chen; Marco Dauriz; Joseph A.C. Delaney; Todd L. Edwards; Daniel S. Evans; Michele K. Evans; Leslie A. Lange; Aaron Leong; Jingmin Liu; Yongmei Liu; Uma Nayak; Sanjay R. Patel; Bianca C. Porneala; Laura J. Rasmussen-Torvik; Marieke B. Snijder; Sarah C. Stallings; Toshiko Tanaka; Lisa R. Yanek; Wei Zhao; Diane M. Becker; Lawrence F. Bielak; Mary L. Biggs; Erwin P. Bottinger; Donald W. Bowden; Guanjie Chen; Adolfo Correa; David J. Couper; Dana C. Crawford; Mary Cushman; John D. Eicher; Myriam Fornage; Nora Franceschini; Yi Ping Fu; Mark O. Goodarzi; Omri Gottesman; Kazuo Hara; Tamara B. Harris; Richard A. Jensen; Andrew D. Johnson; Min A. Jhun; Andrew J. Karter; Margaux F. Keller; Abel N. Kho; Jorge R. Kizer; Ronald M. Krauss; Carl D. Langefeld; Xiaohui Li; Jingling Liang; Simin Liu; William L. Lowe; Thomas H. Mosley; Kari E. North; Jennifer A. Pacheco; Patricia A. Peyser; Alan L. Patrick; Kenneth M. Rice; Elizabeth Selvin; Mario Sims; Jennifer A. Smith; Salman M. Tajuddin; Dhananjay Vaidya; Mary P. Wren; Jie Yao; Xiaofeng Zhu; Julie T. Ziegler; Joseph M. Zmuda; Alan B. Zonderman; Aeilko H. Zwinderman; Adebowale Adeyemo; Eric Boerwinkle; Luigi Ferrucci; M. Geoffrey Hayes; Sharon L.R. Kardia; Iva Miljkovic; James S. Pankow; Charles N. Rotimi; Michele M. Sale; Lynne E. Wagenknecht; Donna K. Arnett; Yii Der Ida Chen; Michael A. Nalls; Michael A. Province; W. H.Linda Kao; David S. Siscovick; Bruce M. Psaty; James G. Wilson; Ruth J.F. Loos; Josée Dupuis; Stephen S. Rich; Jose C. Florez; Jerome I. Rotter; Andrew P. Morris; James B. Meigs

doi:10.1016/j.ajhg.2016.05.006

Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin

Ching Ti Liu, Sridharan Raghavan, Nisa Maruthur, Edmond Kato Kabagambe, Jaeyoung Hong, Maggie C.Y. Ng, Marie France Hivert, Yingchang Lu, Ping An, Amy R. Bentley, Anne M. Drolet, Kyle J. Gaulton, Xiuqing Guo, Loren L. Armstrong, Marguerite R. Irvin, Man Li, Leonard Lipovich, Denis V. Rybin, Kent D. Taylor, Charles AgyemangNicholette D. Palmer, Brian E. Cade, Wei Min Chen, Marco Dauriz, Joseph A.C. Delaney, Todd L. Edwards, Daniel S. Evans, Michele K. Evans, Leslie A. Lange, Aaron Leong, Jingmin Liu, Yongmei Liu, Uma Nayak, Sanjay R. Patel, Bianca C. Porneala, Laura J. Rasmussen-Torvik, Marieke B. Snijder, Sarah C. Stallings, Toshiko Tanaka, Lisa R. Yanek, Wei Zhao, Diane M. Becker, Lawrence F. Bielak, Mary L. Biggs, Erwin P. Bottinger, Donald W. Bowden, Guanjie Chen, Adolfo Correa, David J. Couper, Dana C. Crawford, Mary Cushman, John D. Eicher, Myriam Fornage, Nora Franceschini, Yi Ping Fu, Mark O. Goodarzi, Omri Gottesman, Kazuo Hara, Tamara B. Harris, Richard A. Jensen, Andrew D. Johnson, Min A. Jhun, Andrew J. Karter, Margaux F. Keller, Abel N. Kho, Jorge R. Kizer, Ronald M. Krauss, Carl D. Langefeld, Xiaohui Li, Jingling Liang, Simin Liu, William L. Lowe, Thomas H. Mosley, Kari E. North, Jennifer A. Pacheco, Patricia A. Peyser, Alan L. Patrick, Kenneth M. Rice, Elizabeth Selvin, Mario Sims, Jennifer A. Smith, Salman M. Tajuddin, Dhananjay Vaidya, Mary P. Wren, Jie Yao, Xiaofeng Zhu, Julie T. Ziegler, Joseph M. Zmuda, Alan B. Zonderman, Aeilko H. Zwinderman, Adebowale Adeyemo, Eric Boerwinkle, Luigi Ferrucci, M. Geoffrey Hayes, Sharon L.R. Kardia, Iva Miljkovic, James S. Pankow, Charles N. Rotimi, Michele M. Sale, Lynne E. Wagenknecht, Donna K. Arnett, Yii Der Ida Chen, Michael A. Nalls, Michael A. Province, W. H.Linda Kao, David S. Siscovick, Bruce M. Psaty, James G. Wilson, Ruth J.F. Loos, Josée Dupuis, Stephen S. Rich, Jose C. Florez, Jerome I. Rotter, Andrew P. Morris, James B. Meigs

Medicine

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

44 Scopus citations

Abstract

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

Original language	English (US)
Pages (from-to)	56-75
Number of pages	20
Journal	American Journal of Human Genetics
Volume	99
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2016.05.006
State	Published - Jul 7 2016

ASJC Scopus subject areas

Genetics
Genetics(clinical)

UN SDGs

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

Access to Document

10.1016/j.ajhg.2016.05.006

Cite this

Liu, C. T., Raghavan, S., Maruthur, N., Kabagambe, E. K., Hong, J., Ng, M. C. Y., Hivert, M. F., Lu, Y., An, P., Bentley, A. R., Drolet, A. M., Gaulton, K. J., Guo, X., Armstrong, L. L., Irvin, M. R., Li, M., Lipovich, L., Rybin, D. V., Taylor, K. D., ... Meigs, J. B. (2016). Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin. American Journal of Human Genetics, 99(1), 56-75. https://doi.org/10.1016/j.ajhg.2016.05.006

Liu, CT, Raghavan, S, Maruthur, N, Kabagambe, EK, Hong, J, Ng, MCY, Hivert, MF, Lu, Y, An, P, Bentley, AR, Drolet, AM, Gaulton, KJ, Guo, X, Armstrong, LL, Irvin, MR, Li, M, Lipovich, L, Rybin, DV, Taylor, KD, Agyemang, C, Palmer, ND, Cade, BE, Chen, WM, Dauriz, M, Delaney, JAC, Edwards, TL, Evans, DS, Evans, MK, Lange, LA, Leong, A, Liu, J, Liu, Y, Nayak, U, Patel, SR, Porneala, BC, Rasmussen-Torvik, LJ, Snijder, MB, Stallings, SC, Tanaka, T, Yanek, LR, Zhao, W, Becker, DM, Bielak, LF, Biggs, ML, Bottinger, EP, Bowden, DW, Chen, G, Correa, A, Couper, DJ, Crawford, DC, Cushman, M, Eicher, JD, Fornage, M, Franceschini, N, Fu, YP, Goodarzi, MO, Gottesman, O, Hara, K, Harris, TB, Jensen, RA, Johnson, AD, Jhun, MA, Karter, AJ, Keller, MF, Kho, AN, Kizer, JR, Krauss, RM, Langefeld, CD, Li, X, Liang, J, Liu, S, Lowe, WL, Mosley, TH, North, KE, Pacheco, JA, Peyser, PA, Patrick, AL, Rice, KM, Selvin, E, Sims, M, Smith, JA, Tajuddin, SM, Vaidya, D, Wren, MP, Yao, J, Zhu, X, Ziegler, JT, Zmuda, JM, Zonderman, AB, Zwinderman, AH, Adeyemo, A, Boerwinkle, E, Ferrucci, L, Hayes, MG, Kardia, SLR, Miljkovic, I, Pankow, JS, Rotimi, CN, Sale, MM, Wagenknecht, LE, Arnett, DK, Chen, YDI, Nalls, MA, Province, MA, Kao, WHL, Siscovick, DS, Psaty, BM, Wilson, JG, Loos, RJF, Dupuis, J, Rich, SS, Florez, JC, Rotter, JI, Morris, AP & Meigs, JB 2016, 'Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin', American Journal of Human Genetics, vol. 99, no. 1, pp. 56-75. https://doi.org/10.1016/j.ajhg.2016.05.006

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abstract = "Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.",

author = "Liu, {Ching Ti} and Sridharan Raghavan and Nisa Maruthur and Kabagambe, {Edmond Kato} and Jaeyoung Hong and Ng, {Maggie C.Y.} and Hivert, {Marie France} and Yingchang Lu and Ping An and Bentley, {Amy R.} and Drolet, {Anne M.} and Gaulton, {Kyle J.} and Xiuqing Guo and Armstrong, {Loren L.} and Irvin, {Marguerite R.} and Man Li and Leonard Lipovich and Rybin, {Denis V.} and Taylor, {Kent D.} and Charles Agyemang and Palmer, {Nicholette D.} and Cade, {Brian E.} and Chen, {Wei Min} and Marco Dauriz and Delaney, {Joseph A.C.} and Edwards, {Todd L.} and Evans, {Daniel S.} and Evans, {Michele K.} and Lange, {Leslie A.} and Aaron Leong and Jingmin Liu and Yongmei Liu and Uma Nayak and Patel, {Sanjay R.} and Porneala, {Bianca C.} and Rasmussen-Torvik, {Laura J.} and Snijder, {Marieke B.} and Stallings, {Sarah C.} and Toshiko Tanaka and Yanek, {Lisa R.} and Wei Zhao and Becker, {Diane M.} and Bielak, {Lawrence F.} and Biggs, {Mary L.} and Bottinger, {Erwin P.} and Bowden, {Donald W.} and Guanjie Chen and Adolfo Correa and Couper, {David J.} and Crawford, {Dana C.} and Mary Cushman and Eicher, {John D.} and Myriam Fornage and Nora Franceschini and Fu, {Yi Ping} and Goodarzi, {Mark O.} and Omri Gottesman and Kazuo Hara and Harris, {Tamara B.} and Jensen, {Richard A.} and Johnson, {Andrew D.} and Jhun, {Min A.} and Karter, {Andrew J.} and Keller, {Margaux F.} and Kho, {Abel N.} and Kizer, {Jorge R.} and Krauss, {Ronald M.} and Langefeld, {Carl D.} and Xiaohui Li and Jingling Liang and Simin Liu and Lowe, {William L.} and Mosley, {Thomas H.} and North, {Kari E.} and Pacheco, {Jennifer A.} and Peyser, {Patricia A.} and Patrick, {Alan L.} and Rice, {Kenneth M.} and Elizabeth Selvin and Mario Sims and Smith, {Jennifer A.} and Tajuddin, {Salman M.} and Dhananjay Vaidya and Wren, {Mary P.} and Jie Yao and Xiaofeng Zhu and Ziegler, {Julie T.} and Zmuda, {Joseph M.} and Zonderman, {Alan B.} and Zwinderman, {Aeilko H.} and Adebowale Adeyemo and Eric Boerwinkle and Luigi Ferrucci and Hayes, {M. Geoffrey} and Kardia, {Sharon L.R.} and Iva Miljkovic and Pankow, {James S.} and Rotimi, {Charles N.} and Sale, {Michele M.} and Wagenknecht, {Lynne E.} and Arnett, {Donna K.} and Chen, {Yii Der Ida} and Nalls, {Michael A.} and Province, {Michael A.} and Kao, {W. H.Linda} and Siscovick, {David S.} and Psaty, {Bruce M.} and Wilson, {James G.} and Loos, {Ruth J.F.} and Jos{\'e}e Dupuis and Rich, {Stephen S.} and Florez, {Jose C.} and Rotter, {Jerome I.} and Morris, {Andrew P.} and Meigs, {James B.}",

note = "Publisher Copyright: {\textcopyright} 2016 American Society of Human Genetics",

year = "2016",

month = jul,

day = "7",

doi = "10.1016/j.ajhg.2016.05.006",

language = "English (US)",

volume = "99",

pages = "56--75",

journal = "American Journal of Human Genetics",

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TY - JOUR

T1 - Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin

AU - Liu, Ching Ti

AU - Raghavan, Sridharan

AU - Maruthur, Nisa

AU - Kabagambe, Edmond Kato

AU - Hong, Jaeyoung

AU - Ng, Maggie C.Y.

AU - Hivert, Marie France

AU - Lu, Yingchang

AU - An, Ping

AU - Bentley, Amy R.

AU - Drolet, Anne M.

AU - Gaulton, Kyle J.

AU - Guo, Xiuqing

AU - Armstrong, Loren L.

AU - Irvin, Marguerite R.

AU - Li, Man

AU - Lipovich, Leonard

AU - Rybin, Denis V.

AU - Taylor, Kent D.

AU - Agyemang, Charles

AU - Palmer, Nicholette D.

AU - Cade, Brian E.

AU - Chen, Wei Min

AU - Dauriz, Marco

AU - Delaney, Joseph A.C.

AU - Edwards, Todd L.

AU - Evans, Daniel S.

AU - Evans, Michele K.

AU - Lange, Leslie A.

AU - Leong, Aaron

AU - Liu, Jingmin

AU - Liu, Yongmei

AU - Nayak, Uma

AU - Patel, Sanjay R.

AU - Porneala, Bianca C.

AU - Rasmussen-Torvik, Laura J.

AU - Snijder, Marieke B.

AU - Stallings, Sarah C.

AU - Tanaka, Toshiko

AU - Yanek, Lisa R.

AU - Zhao, Wei

AU - Becker, Diane M.

AU - Bielak, Lawrence F.

AU - Biggs, Mary L.

AU - Bottinger, Erwin P.

AU - Bowden, Donald W.

AU - Chen, Guanjie

AU - Correa, Adolfo

AU - Couper, David J.

AU - Crawford, Dana C.

AU - Cushman, Mary

AU - Eicher, John D.

AU - Fornage, Myriam

AU - Franceschini, Nora

AU - Fu, Yi Ping

AU - Goodarzi, Mark O.

AU - Gottesman, Omri

AU - Hara, Kazuo

AU - Harris, Tamara B.

AU - Jensen, Richard A.

AU - Johnson, Andrew D.

AU - Jhun, Min A.

AU - Karter, Andrew J.

AU - Keller, Margaux F.

AU - Kho, Abel N.

AU - Kizer, Jorge R.

AU - Krauss, Ronald M.

AU - Langefeld, Carl D.

AU - Li, Xiaohui

AU - Liang, Jingling

AU - Liu, Simin

AU - Lowe, William L.

AU - Mosley, Thomas H.

AU - North, Kari E.

AU - Pacheco, Jennifer A.

AU - Peyser, Patricia A.

AU - Patrick, Alan L.

AU - Rice, Kenneth M.

AU - Selvin, Elizabeth

AU - Sims, Mario

AU - Smith, Jennifer A.

AU - Tajuddin, Salman M.

AU - Vaidya, Dhananjay

AU - Wren, Mary P.

AU - Yao, Jie

AU - Zhu, Xiaofeng

AU - Ziegler, Julie T.

AU - Zmuda, Joseph M.

AU - Zonderman, Alan B.

AU - Zwinderman, Aeilko H.

AU - Adeyemo, Adebowale

AU - Boerwinkle, Eric

AU - Ferrucci, Luigi

AU - Hayes, M. Geoffrey

AU - Kardia, Sharon L.R.

AU - Miljkovic, Iva

AU - Pankow, James S.

AU - Rotimi, Charles N.

AU - Sale, Michele M.

AU - Wagenknecht, Lynne E.

AU - Arnett, Donna K.

AU - Chen, Yii Der Ida

AU - Nalls, Michael A.

AU - Province, Michael A.

AU - Kao, W. H.Linda

AU - Siscovick, David S.

AU - Psaty, Bruce M.

AU - Wilson, James G.

AU - Loos, Ruth J.F.

AU - Dupuis, Josée

AU - Rich, Stephen S.

AU - Florez, Jose C.

AU - Rotter, Jerome I.

AU - Morris, Andrew P.

AU - Meigs, James B.

PY - 2016/7/7

Y1 - 2016/7/7

N2 - Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

AB - Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

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