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Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2016-06-16 , DOI: 10.1016/j.ajhg.2016.05.006
Ching-Ti Liu 1 , Sridharan Raghavan 2 , Nisa Maruthur 3 , Edmond Kato Kabagambe 4 , Jaeyoung Hong 1 , Maggie C Y Ng 5 , Marie-France Hivert 6 , Yingchang Lu 7 , Ping An 8 , Amy R Bentley 9 , Anne M Drolet 10 , Kyle J Gaulton 11 , Xiuqing Guo 12 , Loren L Armstrong 13 , Marguerite R Irvin 14 , Man Li 15 , Leonard Lipovich 16 , Denis V Rybin 1 , Kent D Taylor 12 , Charles Agyemang 17 , Nicholette D Palmer 18 , Brian E Cade 19 , Wei-Min Chen 20 , Marco Dauriz 21 , Joseph A C Delaney 22 , Todd L Edwards 4 , Daniel S Evans 23 , Michele K Evans 24 , Leslie A Lange 25 , Aaron Leong 26 , Jingmin Liu 27 , Yongmei Liu 28 , Uma Nayak 20 , Sanjay R Patel 29 , Bianca C Porneala 26 , Laura J Rasmussen-Torvik 30 , Marieke B Snijder 17 , Sarah C Stallings 31 , Toshiko Tanaka 32 , Lisa R Yanek 33 , Wei Zhao 34 , Diane M Becker 35 , Lawrence F Bielak 34 , Mary L Biggs 36 , Erwin P Bottinger 37 , Donald W Bowden 38 , Guanjie Chen 9 , Adolfo Correa 39 , David J Couper 40 , Dana C Crawford 41 , Mary Cushman 42 , John D Eicher 43 , Myriam Fornage 44 , Nora Franceschini 45 , Yi-Ping Fu 46 , Mark O Goodarzi 47 , Omri Gottesman 37 , Kazuo Hara 48 , Tamara B Harris 49 , Richard A Jensen 50 , Andrew D Johnson 51 , Min A Jhun 34 , Andrew J Karter 52 , Margaux F Keller 53 , Abel N Kho 13 , Jorge R Kizer 54 , Ronald M Krauss 55 , Carl D Langefeld 56 , Xiaohui Li 12 , Jingling Liang 57 , Simin Liu 58 , William L Lowe 13 , Thomas H Mosley 59 , Kari E North 45 , Jennifer A Pacheco 13 , Patricia A Peyser 34 , Alan L Patrick 60 , Kenneth M Rice 61 , Elizabeth Selvin 62 , Mario Sims 39 , Jennifer A Smith 34 , Salman M Tajuddin 24 , Dhananjay Vaidya 63 , Mary P Wren 64 , Jie Yao 12 , Xiaofeng Zhu 57 , Julie T Ziegler 56 , Joseph M Zmuda 65 , Alan B Zonderman 66 , Aeilko H Zwinderman 17 , , , , , , Adebowale Adeyemo 9 , Eric Boerwinkle 44 , Luigi Ferrucci 32 , M Geoffrey Hayes 13 , Sharon L R Kardia 34 , Iva Miljkovic 65 , James S Pankow 67 , Charles N Rotimi 9 , Michele M Sale 20 , Lynne E Wagenknecht 68 , Donna K Arnett 69 , Yii-Der Ida Chen 12 , Michael A Nalls 70 , , Michael A Province 8 , W H Linda Kao 15 , David S Siscovick 71 , Bruce M Psaty 72 , James G Wilson 73 , Ruth J F Loos 74 , Josée Dupuis 75 , Stephen S Rich 20 , Jose C Florez 76 , Jerome I Rotter 12 , Andrew P Morris 77 , James B Meigs 26
Affiliation  

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.

中文翻译:


跨种族荟萃分析和功能注释阐明了空腹血糖和胰岛素的遗传结构。



对非洲血统 (AA) 个体中 2 型糖尿病 (T2D) 相关数量性状空腹血糖 (FG) 和胰岛素 (FI) 的遗传基础的了解有限。在 AA (n = 20,209) 和欧洲血统 (EA; n = 57,292) 的非糖尿病受试者中,我们对 54 个已建立的 EA FG 或 FI 基因座进行了跨种族 (AA+EA) 精细定位,并进行了详细的功能注释、评估它们与 AA 个体的相关性,并通过跨种族 (AA+EA) 荟萃分析寻找以前未描述的基因座。我们缩小了驱动 22/54 EA 相关位点关联信号的可信变体集; 18/22 可信组与活性胰岛特异性增强子或转录因子 (TF) 结合位点重叠,21/22 包含至少一个 TF 基序。在 54 个 EA 相关位点中,23 个在 EA 和 AA 之间共享。与另外 10,096 个 AA 个体的复制鉴定出两个先前未描述的 FI 位点:chrX FAM133A (rs213676) 和 chr5 PELO (rs6450057)。带有调控注释的跨种族分析阐明了血糖特征的遗传结构,并建议将基因调控作为推进 T2D 精准医学的目标。我们利用最先进的功能注释并实施跨种族关联分析来发现和精细定位的方法为进一步跟踪和表征复杂性状位点的 GWAS 信号提供了一个框架。
更新日期:2019-11-01
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