Meta-Analysis

. 2016 Jul 7;99(1):56-75.

doi: 10.1016/j.ajhg.2016.05.006. Epub 2016 Jun 16.

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

Ching-Ti Liu¹, Sridharan Raghavan², Nisa Maruthur³, Edmond Kato Kabagambe⁴, Jaeyoung Hong⁵, Maggie C Y Ng⁶, Marie-France Hivert⁷, Yingchang Lu⁸, Ping An⁹, Amy R Bentley¹⁰, Anne M Drolet¹¹, Kyle J Gaulton¹², Xiuqing Guo¹³, Loren L Armstrong¹⁴, Marguerite R Irvin¹⁵, Man Li¹⁶, Leonard Lipovich¹⁷, Denis V Rybin⁵, Kent D Taylor¹³, Charles Agyemang¹⁸, Nicholette D Palmer¹⁹, Brian E Cade²⁰, Wei-Min Chen²¹, Marco Dauriz²², Joseph A C Delaney²³, Todd L Edwards⁴, Daniel S Evans²⁴, Michele K Evans²⁵, Leslie A Lange²⁶, Aaron Leong²⁷, Jingmin Liu²⁸, Yongmei Liu²⁹, Uma Nayak²¹, Sanjay R Patel³⁰, Bianca C Porneala²⁷, Laura J Rasmussen-Torvik³¹, Marieke B Snijder¹⁸, Sarah C Stallings³², Toshiko Tanaka³³, Lisa R Yanek³⁴, Wei Zhao³⁵, Diane M Becker³⁶, Lawrence F Bielak³⁵, Mary L Biggs³⁷, Erwin P Bottinger³⁸, Donald W Bowden³⁹, Guanjie Chen¹⁰, Adolfo Correa⁴⁰, David J Couper⁴¹, Dana C Crawford⁴², Mary Cushman⁴³, John D Eicher⁴⁴, Myriam Fornage⁴⁵, Nora Franceschini⁴⁶, Yi-Ping Fu⁴⁷, Mark O Goodarzi⁴⁸, Omri Gottesman³⁸, Kazuo Hara⁴⁹, Tamara B Harris⁵⁰, Richard A Jensen⁵¹, Andrew D Johnson⁵², Min A Jhun³⁵, Andrew J Karter⁵³, Margaux F Keller⁵⁴, Abel N Kho¹⁴, Jorge R Kizer⁵⁵, Ronald M Krauss⁵⁶, Carl D Langefeld⁵⁷, Xiaohui Li¹³, Jingling Liang⁵⁸, Simin Liu⁵⁹, William L Lowe Jr¹⁴, Thomas H Mosley⁶⁰, Kari E North⁴⁶, Jennifer A Pacheco¹⁴, Patricia A Peyser³⁵, Alan L Patrick⁶¹, Kenneth M Rice⁶², Elizabeth Selvin⁶³, Mario Sims⁴⁰, Jennifer A Smith³⁵, Salman M Tajuddin²⁵, Dhananjay Vaidya⁶⁴, Mary P Wren⁶⁵, Jie Yao¹³, Xiaofeng Zhu⁵⁸, Julie T Ziegler⁵⁷, Joseph M Zmuda⁶⁶, Alan B Zonderman⁶⁷, Aeilko H Zwinderman¹⁸; AAAG Consortium; CARe Consortium; COGENT-BP Consortium; eMERGE Consortium; MEDIA Consortium; Adebowale Adeyemo¹⁰, Eric Boerwinkle⁴⁵, Luigi Ferrucci³³, M Geoffrey Hayes¹⁴, Sharon L R Kardia³⁵, Iva Miljkovic⁶⁶, James S Pankow⁶⁸, Charles N Rotimi¹⁰, Michele M Sale²¹, Lynne E Wagenknecht⁶⁹, Donna K Arnett⁷⁰, Yii-Der Ida Chen¹³, Michael A Nalls⁷¹; MAGIC Consortium; Michael A Province⁹, W H Linda Kao¹⁶, David S Siscovick⁷², Bruce M Psaty⁷³, James G Wilson⁷⁴, Ruth J F Loos⁷⁵, Josée Dupuis⁷⁶, Stephen S Rich²¹, Jose C Florez⁷⁷, Jerome I Rotter¹³, Andrew P Morris⁷⁸, James B Meigs⁷⁹

Affiliations

¹ Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA. Electronic address: ctliu@bu.edu.
² 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.
³ 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.
⁴ Division of Epidemiology, Department of Medicine, School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37203, USA.
⁵ Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ Division of Statistical Genomics, Department of Genetics, School of Medicine, Washington University, St Louis, MO 63108, USA.
¹⁰ Center for Research on Genomics and Global Health, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
¹¹ Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
¹² Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
¹³ Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
¹⁴ Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
¹⁵ Department of Epidemiology, School of Public Health, University of Alabama - Birmingham, Birmingham, AL 35294, USA.
¹⁶ Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
¹⁷ 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.
¹⁸ Department of Public Health, Academic Medical Center Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands.
¹⁹ 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.
²⁰ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
²¹ Center for Public Health Genomics, Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
²² Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy.
²³ Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
²⁴ California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA.
²⁵ Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
²⁶ Department of Genetics, University of North Carolina, Chapel Hill, NC 27607, USA.
²⁷ Division of General Internal Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
²⁸ Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
²⁹ Center for Human Genetics, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
³⁰ Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
³¹ Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
³² Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN 37203, USA.
³³ Translational Gerontology Branch, National Institute of Aging at Harbor Hospital, Baltimore, MD 21225, USA.
³⁴ GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
³⁵ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
³⁶ 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.
³⁷ 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.
³⁸ The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³⁹ 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.
⁴⁰ Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁴¹ Collaborative Studies Coordinating Center, Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27514, USA.
⁴² Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
⁴³ Department of Medicine and Pathology, University of Vermont, College of Medicine, Burlington, VT 05405, USA.
⁴⁴ 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.
⁴⁵ Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁴⁶ Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
⁴⁷ Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, NIH, Framingham, MA 01702, USA.
⁴⁸ Division of Endocrinology, Diabetes & Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁴⁹ 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.
⁵⁰ Laboratory of Epidemiology and Population Sciences, NIH, Bethesda, MD 20892, USA.
⁵¹ Cardiovascular Health Research Unit, Department of Medicine, School of Medicine, University of Washington, Seattle, WA 98195, USA.
⁵² Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Framingham, MA 01702, USA.
⁵³ Division of Research, Kaiser Permanente, Northern California Region, Oakland, CA 94612, USA.
⁵⁴ Department of Genetics and Pharmacogenomics, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
⁵⁵ 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.
⁵⁶ Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
⁵⁷ 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.
⁵⁸ Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
⁵⁹ Department of Epidemiology, Brown University, Providence, RI 02912, USA; Department of Medicine, Brown University, Providence, RI 02903, USA.
⁶⁰ Division of Geriatrics/Gerontology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁶¹ Tobago Health Studies Office, Scarborough, Tobago, Trinidad and Tobago.
⁶² Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
⁶³ 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.
⁶⁴ 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.
⁶⁵ Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
⁶⁶ Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
⁶⁷ Behavioral Epidemiology Section, Laboratory of Epidemiology & Population Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, US.
⁶⁸ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA.
⁶⁹ Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
⁷⁰ University of Kentucky College of Public Health, Lexington, KY 40563, USA.
⁷¹ Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
⁷² 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.
⁷³ 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.
⁷⁴ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁷⁵ 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.
⁷⁶ 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.
⁷⁷ 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.
⁷⁸ 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.
⁷⁹ Division of General Internal Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: jmeigs@partners.org.

PMID: 27321945
PMCID: PMC5005440
DOI: 10.1016/j.ajhg.2016.05.006

Meta-Analysis

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

Ching-Ti Liu et al. Am J Hum Genet. 2016.

. 2016 Jul 7;99(1):56-75.

doi: 10.1016/j.ajhg.2016.05.006. Epub 2016 Jun 16.

Authors

Affiliations

¹ Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA. Electronic address: ctliu@bu.edu.
² 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.
³ 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.
⁴ Division of Epidemiology, Department of Medicine, School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37203, USA.
⁵ Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ Division of Statistical Genomics, Department of Genetics, School of Medicine, Washington University, St Louis, MO 63108, USA.
¹⁰ Center for Research on Genomics and Global Health, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
¹¹ Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
¹² Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
¹³ Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
¹⁴ Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
¹⁵ Department of Epidemiology, School of Public Health, University of Alabama - Birmingham, Birmingham, AL 35294, USA.
¹⁶ Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
¹⁷ 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.
¹⁸ Department of Public Health, Academic Medical Center Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands.
¹⁹ 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.
²⁰ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
²¹ Center for Public Health Genomics, Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
²² Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy.
²³ Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
²⁴ California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA.
²⁵ Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
²⁶ Department of Genetics, University of North Carolina, Chapel Hill, NC 27607, USA.
²⁷ Division of General Internal Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
²⁸ Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
²⁹ Center for Human Genetics, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
³⁰ Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
³¹ Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
³² Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN 37203, USA.
³³ Translational Gerontology Branch, National Institute of Aging at Harbor Hospital, Baltimore, MD 21225, USA.
³⁴ GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
³⁵ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
³⁶ 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.
³⁷ 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.
³⁸ The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³⁹ 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.
⁴⁰ Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁴¹ Collaborative Studies Coordinating Center, Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27514, USA.
⁴² Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
⁴³ Department of Medicine and Pathology, University of Vermont, College of Medicine, Burlington, VT 05405, USA.
⁴⁴ 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.
⁴⁵ Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁴⁶ Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
⁴⁷ Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, NIH, Framingham, MA 01702, USA.
⁴⁸ Division of Endocrinology, Diabetes & Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁴⁹ 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.
⁵⁰ Laboratory of Epidemiology and Population Sciences, NIH, Bethesda, MD 20892, USA.
⁵¹ Cardiovascular Health Research Unit, Department of Medicine, School of Medicine, University of Washington, Seattle, WA 98195, USA.
⁵² Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Framingham, MA 01702, USA.
⁵³ Division of Research, Kaiser Permanente, Northern California Region, Oakland, CA 94612, USA.
⁵⁴ Department of Genetics and Pharmacogenomics, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
⁵⁵ 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.
⁵⁶ Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
⁵⁷ 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.
⁵⁸ Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
⁵⁹ Department of Epidemiology, Brown University, Providence, RI 02912, USA; Department of Medicine, Brown University, Providence, RI 02903, USA.
⁶⁰ Division of Geriatrics/Gerontology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁶¹ Tobago Health Studies Office, Scarborough, Tobago, Trinidad and Tobago.
⁶² Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
⁶³ 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.
⁶⁴ 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.
⁶⁵ Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
⁶⁶ Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
⁶⁷ Behavioral Epidemiology Section, Laboratory of Epidemiology & Population Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, US.
⁶⁸ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA.
⁶⁹ Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
⁷⁰ University of Kentucky College of Public Health, Lexington, KY 40563, USA.
⁷¹ Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
⁷² 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.
⁷³ 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.
⁷⁴ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁷⁵ 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.
⁷⁶ 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.
⁷⁷ 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.
⁷⁸ 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.
⁷⁹ Division of General Internal Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: jmeigs@partners.org.

PMID: 27321945
PMCID: PMC5005440
DOI: 10.1016/j.ajhg.2016.05.006

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.

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Figures

**Figure 1**
Trans-ethnic Analysis of Glycemic Quantitative Loci Provides Narrowed Intervals Spanned by the 99% Credible Set Data are 500 kb regional association plots for fasting glucose at *FOXA2*, centered at the index SNP identified from European ancestry (EA) samples. The x axis denotes genomic position and the y axis denotes the log (BF), recombination rate, and varLD information (a measure to quantify LD variation differences comparing populations). The red diamond data point represents the index SNP within the region previously reported from EA samples. The color of each data point indicates its LD value (r²) with the index SNP based on HapMap2 (YRI for AA results and CEU for EA results): white, r² not available; blue, r² = 0.0–0.2; brown, r² = 0.2–0.5; orange, r² = 0.5–0.8; red, r² = 0.8–1.0. The blue line represents the recombination rate. The green line shows the varLD score at each SNP and is highlighted with dark brown if the varLD score is >95^th percentile of the genome-wide varLD score, comparing LD information between YRI and CEU HapMap2 samples. The interval spanned by the 99% credible set is highlighted in pink. (A) Association results for fasting glucose in the *FOXA2* region in EA individuals. The 99% credible set contains 40 SNPs that span an interval of 46,365 bp. (B) Association results for fasting glucose in the *FOXA2* region in AA individuals. The association signal is weaker than in EA samples, leading to a wider interval spanned by the 99% credible set. (C) Association results for fasting glucose in the *FOXA2* region in both EA and AA individuals. The 99% credible set contains 2 SNPs and spans an interval of 3,872 bp, a 95% reduction in the number of SNPs and a 91.6% reduction in the length of the credible set interval.

**Figure 2**
Trans-ethnic Fine-Mapping of Glycemic Quantitative Trait Loci Highlights Overlap between Trait-Associated SNPs and Predicted Regulatory Function (A) Analysis for enrichment of posterior probabilities in SNPs overlapping transcription factor binding sites (TFBSs) and cell-type-specific enhancer and promoter marks at 22 (13 FG, 8 FI, and 1 both FG and FI) substantially narrowed 99% credible sets. x axis shows fold-enrichment above null, the y axis shows –log₁₀(P) for enrichment, and FI and FG are indicated by yellow and blue points, respectively. TFBSs and cell types with enhancer or promoter marks with p value for enrichment below 0.01 are labeled. (B) Regional association plots for fasting glucose after trans-ethnic analysis demonstrating overlap between regulatory annotation and narrowed credible regions at the *FOXA2* locus. (C) Regional association plots for fasting glucose after trans-ethnic analysis demonstrating overlap between regulatory annotation and narrowed credible regions at the *CRY2* locus. (B and C) The index SNP in European ancestry (MAGIC) is represented by a diamond; the best SNP in African ancestry (AAGILE) is represented by a triangle. SNPs are colored according to the score assigned in RegulomeDB with lower score corresponding to stronger level of evidence supporting regulatory function; data from the Islet Regulome Browser for the genomic interval is shown below regional association plots. The interval spanned by the 99% credible set using EA data only is represented by combining blue and pink regions; interval spanned by the narrowed 99% credible set after trans-ethnic analysis is shown in pink.

**Figure 3**
Regional Association Plots and Functional Annotation for Two Previously Undescribed Loci (A) Regional association plot of a previously undescribed chromosome X locus associated with fasting insulin in AA individuals. The nearest gene is *FAM133A*. Top panel shows association signal on the y axis (−log(P)) and genomic position on chromosome X on the x axis. The red diamond data point represents the lead SNP (rs213676) within the region. The blue line represents the recombination rate. The color of each data point indicates its LD value (r²) with the lead SNP at the locus based on HapMap2 YRI: white, r² not available; blue, r² = 0.0–0.2; brown, r² = 0.2–0.5; orange, r² = 0.5–0.8; red, r² = 0.8–1.0. The bottom part of the figure shows Islet Regulome Browser data for the genomic interval shown in the regional association plot. (B) Regional association plot of a previously undescribed chromosome 5 locus associated with fasting insulin in trans-ethnic meta-analysis. The nearest gene is *PELO* (also called *ITGA1*). The red diamond data point represents the lead SNP (rs6450057) within the region. The blue line represents the recombination rate. The color of each data point indicates its LD value (r²) with the lead SNP at the locus based on HapMap2: white, r² not available; blue, r² = 0.0–0.2; brown, r² = 0.2–0.5; orange, r² = 0.5–0.8; red, r² = 0.8–1.0.The top two panels show association with −log(P) on the y axis and genomic position on chromosome 5 on the x axis. The top panel shows association in European ancestry (EA) individuals in MAGIC with plotted points colored according to LD with the lead SNP in HapMap CEU individuals; the middle panel shows association in African ancestry (AA) samples with plotted points colored according to LD with lead SNP in HapMap YRI individuals. The bottom panel shows the trans-ethnic association, with log(BF) on the y axis and genomic position on the x axis, and plotted points colored according to LD with lead SNP in HapMap YRI individuals. (C) Comparison of the direction of effect on fasting insulin levels of SNPs at the previously undescribed chromosome 5 locus (*PELO*) comparing EA with AA samples. The product of the sign of the beta-coefficient for FI level and –log(P) for each SNP at the locus in EA samples (MAGIC) and in AA samples (AAGILE) is plotted on the x and y axes, respectively. The red diamond data point represents the lead SNP (rs6450057) within the region. The color of each data point indicates its LD value (r²) with the lead SNP at the locus based on HapMap2 YRI: white, r² not available; blue, r² = 0.0–0.2; brown, r² = 0.2–0.5; orange, r² = 0.5–0.8; red, r² = 0.8–1.0. SNPs exhibit opposite effects on fasting insulin level with similar association p values across the LD spectrum at the locus. (D) Regional association plot of a previously undescribed chromosome 5 locus, with plotted points colored according to RegulomeDB score. The diamond data point represents the lead SNP (rs6450057) within the region; the 99% credible set derived from EA data only is represented by combining the blue and pink boxes; the 99% credible set derived from trans-ethnic analysis is represented by the pink box. Top panel shows a 500 kb genomic span, the lower panel shows a 100 kb genomic span. Data from the Islet RegulomeDB, aligned in the bottom part of the panel, shows binding sites for five transcription factors and regulatory genomic marks in pancreatic islets.

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References

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

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

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