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 & 95 others 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 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

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)56-75
Number of pages20
JournalAmerican Journal of Human Genetics
Volume99
Issue number1
DOIs
StatePublished - Jul 7 2016

Fingerprint

Meta-Analysis
Fasting
Insulin
Glucose
Type 2 Diabetes Mellitus
Transcription Factors
Precision Medicine
Genome-Wide Association Study
Binding Sites
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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

In: American Journal of Human Genetics, Vol. 99, No. 1, 07.07.2016, p. 56-75.

Research output: Contribution to journalArticle

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, J, 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
Liu, Ching Ti ; Raghavan, Sridharan ; Maruthur, Nisa ; Kabagambe, Edmond Kato ; Hong, Jaeyoung ; Ng, Maggie C Y ; Hivert, Marie France ; Lu, Yingchang ; An, Ping ; Bentley, Amy R. ; Drolet, Anne M. ; Gaulton, Kyle J. ; Guo, Xiuqing ; Armstrong, Loren L. ; Irvin, Marguerite R. ; Li, Man ; Lipovich, Leonard ; Rybin, Denis V. ; Taylor, Kent D. ; Agyemang, Charles ; Palmer, Nicholette D. ; Cade, Brian E. ; Chen, Wei Min ; Dauriz, Marco ; Delaney, Joseph A C ; Edwards, Todd L. ; Evans, Daniel S. ; Evans, Michele K. ; Lange, Leslie A. ; Leong, Aaron ; Liu, Jingmin ; Liu, Yongmei ; Nayak, Uma ; Patel, Sanjay R. ; Porneala, Bianca C. ; Rasmussen-Torvik, Laura J. ; Snijder, Marieke B. ; Stallings, Sarah C. ; Tanaka, Toshiko ; Yanek, Lisa R. ; Zhao, Wei ; Becker, Diane M. ; Bielak, Lawrence F. ; Biggs, Mary L. ; Bottinger, Erwin P. ; Bowden, Donald W. ; Chen, Guanjie ; Correa, Adolfo ; Couper, David J. ; Crawford, Dana C. ; Cushman, Mary ; Eicher, John D. ; Fornage, Myriam ; Franceschini, Nora ; Fu, Yi Ping ; Goodarzi, Mark O. ; Gottesman, Omri ; Hara, Kazuo ; Harris, Tamara B. ; Jensen, Richard A. ; Johnson, Andrew D. ; Jhun, Min A. ; Karter, Andrew J. ; Keller, Margaux F. ; Kho, Abel N. ; Kizer, Jorge ; Krauss, Ronald M. ; Langefeld, Carl D. ; Li, Xiaohui ; Liang, Jingling ; Liu, Simin ; Lowe, William L. ; Mosley, Thomas H. ; North, Kari E. ; Pacheco, Jennifer A. ; Peyser, Patricia A. ; Patrick, Alan L. ; Rice, Kenneth M. ; Selvin, Elizabeth ; Sims, Mario ; Smith, Jennifer A. ; Tajuddin, Salman M. ; Vaidya, Dhananjay ; Wren, Mary P. ; Yao, Jie ; Zhu, Xiaofeng ; Ziegler, Julie T. ; Zmuda, Joseph M. ; Zonderman, Alan B. ; Zwinderman, Aeilko H. ; Adeyemo, Adebowale ; Boerwinkle, Eric ; Ferrucci, Luigi ; Hayes, M. Geoffrey ; Kardia, Sharon L R ; Miljkovic, Iva ; Pankow, James S. ; Rotimi, Charles N. ; Sale, Michele M. ; Wagenknecht, Lynne E. ; Arnett, Donna K. ; Chen, Yii Der Ida ; Nalls, Michael A. ; Province, Michael A. ; Kao, W. H Linda ; Siscovick, David S. ; Psaty, Bruce M. ; Wilson, James G. ; Loos, Ruth J F ; Dupuis, Josée ; Rich, Stephen S. ; Florez, Jose C. ; Rotter, Jerome I. ; Morris, Andrew P. ; Meigs, James B. / Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin. In: American Journal of Human Genetics. 2016 ; Vol. 99, No. 1. pp. 56-75.
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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

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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