Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.
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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.
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| Authors | 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 Jr, 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, AAAG Consortium, CARe Consortium, COGENT-BP Consortium, eMERGE Consortium, MEDIA Consortium, 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, MAGIC Consortium, 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 |
| Journal | American journal of human genetics (Am J Hum Genet) Vol. 99 Issue 1 Pg. 56-75 (Jul 07 2016) ISSN: 1537-6605 [Electronic] United States |
| PMID | 27321945 (Publication Type: Journal Article, Meta-Analysis) |
| Copyright | Copyright © 2016 American Society of Human Genetics. All rights reserved. |
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