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

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Liu, Ching-Ti, Raghavan, Sridharan, Maruthur, Nisa, Kabagambe, Edmond Kato, Hong, Jaeyoung, Ng, Maggie CY, Hivert, Marie-France, Lu, Yingchang, An, Ping, Bentley, Amy R et al (show 105 more authors) , 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 AC, 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 R, Krauss, Ronald M, Langefeld, Carl D, Li, Xiaohui, Liang, Jingling, Liu, Simin, Lowe, William L Jr, 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 LR, 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, WH Linda, Siscovick, David S, Psaty, Bruce M, Wilson, James G, Loos, Ruth JF, Dupuis, Josee, Rich, Stephen S, Florez, Jose C, Rotter, Jerome I, Morris, Andrew P and Meigs, James 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). pp. 56-75.

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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.

Item Type:	Article
Uncontrolled Keywords:	AAAG Consortium, CARe Consortium, COGENT-BP Consortium, eMERGE Consortium, MEDIA Consortium, MAGIC Consortium, Islets of Langerhans, Humans, Diabetes Mellitus, Type 2, Insulin Resistance, Insulin, Blood Glucose, Transcription Factors, Fasting, Gene Frequency, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Introns, Female, Male, Enhancer Elements, Genetic, Genome-Wide Association Study, Molecular Sequence Annotation, Ethnicity, Racial Groups, Asian People, White People, Black People
Depositing User:	Symplectic Admin
Date Deposited:	23 Jun 2016 09:04
Last Modified:	13 Feb 2023 21:11
DOI:	10.1016/j.ajhg.2016.05.006
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3001815