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

*Corresponding author for this work

Research output: Contribution to journalArticle

28 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 languageEnglish (US)
Pages (from-to)56-75
Number of pages20
JournalAmerican journal of human genetics
Volume99
Issue number1
DOIs
StatePublished - Jul 7 2016

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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