Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.,American Journal of Human Genetics

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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

Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA.
Division of General Internal Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Veterans Affairs Medical Center, Eastern Colorado Health Care System, Denver, CO 80220, USA; Division of General Internal Medicine, Department of Medicine, University of Colorado School of Medicine, Denver, CO 80220, USA.
Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
Division of Epidemiology, Department of Medicine, School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37203, USA.
Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; Center for Diabetes Research, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA 02215, USA; Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Universite de Sherbrooke, Sherbrooke, QC J1G 0A2, Canada.
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Division of Statistical Genomics, Department of Genetics, School of Medicine, Washington University, St Louis, MO 63108, USA.
Center for Research on Genomics and Global Health, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Department of Epidemiology, School of Public Health, University of Alabama - Birmingham, Birmingham, AL 35294, USA.
Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI 48201, USA; Department of Neurology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Department of Public Health, Academic Medical Center Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands.
Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Center for Public Health Genomics, Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy.
Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA.
Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Department of Genetics, University of North Carolina, Chapel Hill, NC 27607, USA.
Division of General Internal Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Center for Human Genetics, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN 37203, USA.
Translational Gerontology Branch, National Institute of Aging at Harbor Hospital, Baltimore, MD 21225, USA.
GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Health Policy and Management, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA; Cardiovascular Health Research Unit, Department of Medicine, School of Medicine, University of Washington, Seattle, WA 98195, USA.
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; Center for Diabetes Research, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Collaborative Studies Coordinating Center, Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27514, USA.
Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
Department of Medicine and Pathology, University of Vermont, College of Medicine, Burlington, VT 05405, USA.
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Framingham, MA 01702, USA.
Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, NIH, Framingham, MA 01702, USA.
Division of Endocrinology, Diabetes & Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Department of Diabetes, Endocrinology, and Metabolism, Tokyo Medical University, Tokyo 163-0023, Japan.
Laboratory of Epidemiology and Population Sciences, NIH, Bethesda, MD 20892, USA.
Cardiovascular Health Research Unit, Department of Medicine, School of Medicine, University of Washington, Seattle, WA 98195, USA.
Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Framingham, MA 01702, USA.
Division of Research, Kaiser Permanente, Northern California Region, Oakland, CA 94612, USA.
Department of Genetics and Pharmacogenomics, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
Center for Public Health Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
Department of Epidemiology, Brown University, Providence, RI 02912, USA; Department of Medicine, Brown University, Providence, RI 02903, USA.
Division of Geriatrics/Gerontology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Tobago Health Studies Office, Scarborough, Tobago, Trinidad and Tobago.
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA; GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Behavioral Epidemiology Section, Laboratory of Epidemiology & Population Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, US.
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA.
Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
University of Kentucky College of Public Health, Lexington, KY 40563, USA.
Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
Department of Epidemiology, University of Washington, Seattle, WA 98195, USA; Cardiovascular Health Research Unit, Department of Medicine, School of Medicine, University of Washington, Seattle, WA 98195, USA; The New York Academy of Medicine, New York, NY 10029, USA.
Department of Epidemiology, University of Washington, Seattle, WA 98195, USA; Cardiovascular Health Research Unit, Department of Medicine, School of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Health Services, University of Washington, Seattle, WA 98195, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA; National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA.
Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Institute of Translational Medicine, Department of Biostatistics, University of Liverpool, Liverpool L69 3BX, UK.

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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