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.
Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA. Electronic address: ctliu@bu.edu.
Ching-Ti
CT
Liu
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.
Sridharan
S
Raghavan
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.
Nisa
N
Maruthur
Division of Epidemiology, Department of Medicine, School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37203, USA.
Edmond Kato
EK
Kabagambe
Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA.
Jaeyoung
J
Hong
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.
Maggie C Y
MC
Ng
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.
Marie-France
MF
Hivert
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.
Yingchang
Y
Lu
Division of Statistical Genomics, Department of Genetics, School of Medicine, Washington University, St Louis, MO 63108, USA.
Ping
P
An
Center for Research on Genomics and Global Health, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
Amy R
AR
Bentley
Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Anne M
AM
Drolet
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Kyle J
KJ
Gaulton
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Xiuqing
X
Guo
Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Loren L
LL
Armstrong
Department of Epidemiology, School of Public Health, University of Alabama - Birmingham, Birmingham, AL 35294, USA.
Marguerite R
MR
Irvin
Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
Man
M
Li
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.
Leonard
L
Lipovich
Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA.
Denis V
DV
Rybin
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Kent D
KD
Taylor
Department of Public Health, Academic Medical Center Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands.
Charles
C
Agyemang
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.
Nicholette D
ND
Palmer
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Brian E
BE
Cade
Center for Public Health Genomics, Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Wei-Min
WM
Chen
Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy.
Marco
M
Dauriz
Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
Joseph A C
JA
Delaney
Division of Epidemiology, Department of Medicine, School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37203, USA.
Todd L
TL
Edwards
California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA.
Daniel S
DS
Evans
Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Michele K
MK
Evans
Department of Genetics, University of North Carolina, Chapel Hill, NC 27607, USA.
Leslie A
LA
Lange
Division of General Internal Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Aaron
A
Leong
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Jingmin
J
Liu
Center for Human Genetics, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Yongmei
Y
Liu
Center for Public Health Genomics, Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Uma
U
Nayak
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Sanjay R
SR
Patel
Division of General Internal Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Bianca C
BC
Porneala
Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Laura J
LJ
Rasmussen-Torvik
Department of Public Health, Academic Medical Center Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands.
Marieke B
MB
Snijder
Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN 37203, USA.
Sarah C
SC
Stallings
Translational Gerontology Branch, National Institute of Aging at Harbor Hospital, Baltimore, MD 21225, USA.
Toshiko
T
Tanaka
GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
Lisa R
LR
Yanek
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
Wei
W
Zhao
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.
Diane M
DM
Becker
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
Lawrence F
LF
Bielak
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.
Mary L
ML
Biggs
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Erwin P
EP
Bottinger
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.
Donald W
DW
Bowden
Center for Research on Genomics and Global Health, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
Guanjie
G
Chen
Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Adolfo
A
Correa
Collaborative Studies Coordinating Center, Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27514, USA.
David J
DJ
Couper
Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
Dana C
DC
Crawford
Department of Medicine and Pathology, University of Vermont, College of Medicine, Burlington, VT 05405, USA.
Mary
M
Cushman
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.
John D
JD
Eicher
Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Myriam
M
Fornage
Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
Nora
N
Franceschini
Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, NIH, Framingham, MA 01702, USA.
Yi-Ping
YP
Fu
Division of Endocrinology, Diabetes & Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Mark O
MO
Goodarzi
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Omri
O
Gottesman
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.
Kazuo
K
Hara
Laboratory of Epidemiology and Population Sciences, NIH, Bethesda, MD 20892, USA.
Tamara B
TB
Harris
Cardiovascular Health Research Unit, Department of Medicine, School of Medicine, University of Washington, Seattle, WA 98195, USA.
Richard A
RA
Jensen
Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Framingham, MA 01702, USA.
Andrew D
AD
Johnson
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
Min A
MA
Jhun
Division of Research, Kaiser Permanente, Northern California Region, Oakland, CA 94612, USA.
Andrew J
AJ
Karter
Department of Genetics and Pharmacogenomics, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Margaux F
MF
Keller
Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Abel N
AN
Kho
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.
Jorge R
JR
Kizer
Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
Ronald M
RM
Krauss
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.
Carl D
CD
Langefeld
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Xiaohui
X
Li
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
Jingling
J
Liang
Department of Epidemiology, Brown University, Providence, RI 02912, USA; Department of Medicine, Brown University, Providence, RI 02903, USA.
Simin
S
Liu
Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
William L
WL
Lowe
Division of Geriatrics/Gerontology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Thomas H
TH
Mosley
Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
Kari E
KE
North
Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Jennifer A
JA
Pacheco
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
Patricia A
PA
Peyser
Tobago Health Studies Office, Scarborough, Tobago, Trinidad and Tobago.
Alan L
AL
Patrick
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Kenneth M
KM
Rice
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.
Elizabeth
E
Selvin
Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Mario
M
Sims
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
Jennifer A
JA
Smith
Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Salman M
SM
Tajuddin
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.
Dhananjay
D
Vaidya
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Mary P
MP
Wren
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Jie
J
Yao
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
Xiaofeng
X
Zhu
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.
Julie T
JT
Ziegler
Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Joseph M
JM
Zmuda
Behavioral Epidemiology Section, Laboratory of Epidemiology & Population Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, US.
Alan B
AB
Zonderman
Department of Public Health, Academic Medical Center Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands.
Aeilko H
AH
Zwinderman
Center for Research on Genomics and Global Health, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
Adebowale
A
Adeyemo
Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Eric
E
Boerwinkle
Translational Gerontology Branch, National Institute of Aging at Harbor Hospital, Baltimore, MD 21225, USA.
Luigi
L
Ferrucci
Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
M Geoffrey
MG
Hayes
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
Sharon L R
SL
Kardia
Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Iva
I
Miljkovic
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA.
James S
JS
Pankow
Center for Research on Genomics and Global Health, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
Charles N
CN
Rotimi
Center for Public Health Genomics, Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Michele M
MM
Sale
Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Lynne E
LE
Wagenknecht
University of Kentucky College of Public Health, Lexington, KY 40563, USA.
Donna K
DK
Arnett
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Yii-Der Ida
YD
Chen
Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
Michael A
MA
Nalls
Division of Statistical Genomics, Department of Genetics, School of Medicine, Washington University, St Louis, MO 63108, USA.
Michael A
MA
Province
Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
W H Linda
WH
Kao
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.
David S
DS
Siscovick
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.
Bruce M
BM
Psaty
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
James G
JG
Wilson
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.
Ruth J F
RJ
Loos
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.
Josée
J
Dupuis
Center for Public Health Genomics, Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Stephen S
SS
Rich
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.
Jose C
JC
Florez
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Jerome I
JI
Rotter
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.
Andrew P
AP
Morris
Division of General Internal Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: jmeigs@partners.org.
James B
JB
Meigs
D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D001786:Blood Glucose / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005006:Ethnicity / Q000235:genetics*; D005215:Fasting / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D007438:Introns / Q000235:genetics; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D058977:Molecular Sequence Annotation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D044469:Racial Groups / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D044465:White People / Q000235:genetics
D001786:Blood Glucose; D007328:Insulin; D014157:Transcription Factors