Trans-ethnic meta-analysis and functional annotation illuminates the genetic architecture of fasting glucose and insulin

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) f...

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Main Authors: Liu, C, Raghavan, S, Maruthur, N, Kabagambe, E, Hong, J, Ng, M, Hivert, M, Lu, Y, An, P, Bentley, A, Drolet, A, Gaulton, K, Guo, X, Armstrong, L, Irvin, M, Li, M, Lipovich, L, Rybin, D, Taylor, K, Agyemang, C, Palmer, N, Cade, B, Chen, W, Dauriz, M, Delaney, J, Edwards, T, Evans, D, Evans, M, Lange, L, Leong, A, Liu, J, Liu, Y, Nayak, U, Patel, S, Porneala, B, Rasmussen-Torvik, L, Snijder, M, Stallings, S, Tanaka, T, Yanek, L, Zhao, W, Becker, D, Bielak, L, Biggs, M, Bottinger, E, Bowden, D, Chen, G, Correa, A, Couper, D, Crawford, D, Cushman, M, Eicher, J, Fornage, M, Franceschini, N, Fu, Y, Goodarzi, M, Gottesman, O, Hara, K, Harris, T, Jensen, R, Johnson, A, Jhun, M, Karter, A, Keller, M, Kho, A, Kizer, J, Krauss, R, Langefeld, C, Li, X, Liang, J, Liu, S, Lowe, W, Mosley, T, North, K, Pacheco, J, Peyser, P, Patrick, A, Rice, K, Selvin, E, Sims, M, Smith, J, Tajuddin, S, Vaidya, D, Wren, M, Yao, J, Zhu, X, Ziegler, J, Zmuda, J, Zonderman, A, Zwinderman, A, Adeyemo, A, Boerwinkle, E, Ferrucci, L, Hayes, M, Kardia, S, Miljkovic, I, Pankow, J, Rotimi, C, Sale, M, Wagenknecht, L, Arnett, D, Chen, Y, Nalls, M, Province, M, Kao, W, Siscovick, D, Psaty, B, Wilson, J, Loos, R, Dupuis, J, Rich, S, Florez, J, Rotter, J, Morris, A, Meigs, J
Format: Journal article
Language:English
Published: Elsevier 2016
Description
Summary: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.