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) 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.
Liu, C-T; Raghavan, S; Maruthur, N; Kabagambe, EK; Hong, J; Ng, MCY; Hivert, M-F; 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, W-M; 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, Y-P; Goodarzi, MO; Gottesman, O; Hara, K; Harris, TB; Jensen, RA; Johnson, AD; Jhun, MA; Karter, AJ; Keller, MF; Kho, AN; Kizer, JR; 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; AAAG Consortium, ; CARe Consortium, ; COGENT-BP Consortium, ; eMERGE Consortium, ; MEDIA Consortium, ; Adeyemo, A; Boerwinkle, E; Ferrucci, L; Hayes, MG; Kardia, SLR; Miljkovic, I; Pankow, JS; Rotimi, CN; Sale, MM; Wagenknecht, LE; Arnett, DK; Chen, Y-DI; Nalls, MA; MAGIC Consortium, ; Province, MA; Kao, WHL; Siscovick, DS; Psaty, BM; Wilson, JG; Loos, RJF; Dupuis, J; Rich, SS; Florez, JC; Rotter, JI; Morris, AP; Meigs, JB
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