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Am J Hum Genet. 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.

Liu CT1, Raghavan S2, Maruthur N3, Kabagambe EK4, Hong J5, Ng MC6, Hivert MF7, Lu Y8, An P9, Bentley AR10, Drolet AM11, Gaulton KJ12, Guo X13, Armstrong LL14, Irvin MR15, Li M16, Lipovich L17, Rybin DV5, Taylor KD13, Agyemang C18, Palmer ND19, Cade BE20, Chen WM21, Dauriz M22, Delaney JA23, Edwards TL4, Evans DS24, Evans MK25, Lange LA26, Leong A27, Liu J28, Liu Y29, Nayak U21, Patel SR30, Porneala BC27, Rasmussen-Torvik LJ31, Snijder MB18, Stallings SC32, Tanaka T33, Yanek LR34, Zhao W35, Becker DM36, Bielak LF35, Biggs ML37, Bottinger EP38, Bowden DW39, Chen G10, Correa A40, Couper DJ41, Crawford DC42, Cushman M43, Eicher JD44, Fornage M45, Franceschini N46, Fu YP47, Goodarzi MO48, Gottesman O38, Hara K49, Harris TB50, Jensen RA51, Johnson AD52, Jhun MA35, Karter AJ53, Keller MF54, Kho AN14, Kizer JR55, Krauss RM56, Langefeld CD57, Li X13, Liang J58, Liu S59, Lowe WL Jr14, Mosley TH60, North KE46, Pacheco JA14, Peyser PA35, Patrick AL61, Rice KM62, Selvin E63, Sims M40, Smith JA35, Tajuddin SM25, Vaidya D64, Wren MP65, Yao J13, Zhu X58, Ziegler JT57, Zmuda JM66, Zonderman AB67, Zwinderman AH18; AAAG Consortium; CARe Consortium; COGENT-BP Consortium; eMERGE Consortium; MEDIA Consortium, Adeyemo A10, Boerwinkle E45, Ferrucci L33, Hayes MG14, Kardia SL35, Miljkovic I66, Pankow JS68, Rotimi CN10, Sale MM21, Wagenknecht LE69, Arnett DK70, Chen YD13, Nalls MA71; MAGIC Consortium, Province MA9, Kao WH16, Siscovick DS72, Psaty BM73, Wilson JG74, Loos RJ75, Dupuis J76, Rich SS21, Florez JC77, Rotter JI13, Morris AP78, Meigs JB79.

Author information

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.

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.

PMID:
27321945
PMCID:
PMC5005440
DOI:
10.1016/j.ajhg.2016.05.006
[Indexed for MEDLINE]
Free PMC Article

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