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Diabetes. 2019 Feb;68(2):441-456. doi: 10.2337/db18-0567. Epub 2018 Nov 28.

Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.

Author information

1
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.
2
Department of Population and Quantitative Health Sciences, Case Western University, Cleveland, OH.
3
Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA.
4
Institute for Translational Genomics and Population Sciences, LA BioMed and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA.
5
Duke-NUS Medical School, Singapore.
6
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
7
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC.
8
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC.
9
Department of Medicine, University of Iceland, Reykjavík, Iceland.
10
Massachusetts Eye and Ear Department of Ophthalmology, Harvard Medical School, Boston, MA.
11
Medical Affairs, Ophthalmology, Sun Pharmaceutical Industries, Inc., Princeton, NJ.
12
Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee School of Medicine, Scotland, U.K.
13
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
14
Laboratory for Endocrinology, Metabolism and Kidney Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
15
Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.
16
Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Nishihara, Japan.
17
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
18
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
19
Department of Ophthalmology, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.
20
Endocrine Unit and Diabetes Unit, Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA.
21
Section of Genetic Medicine, University of Chicago, Chicago, IL.
22
Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
23
Section of Diabetes and Metabolism, Harbor-UCLA Medical Center, University of California, Los Angeles, Los Angeles, CA.
24
Department of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-University of California, Torrance, CA.
25
Department of Medicine, Case Western Reserve University, Cleveland, OH.
26
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH.
27
Division of Nephrology, MetroHealth System, Cleveland, OH.
28
Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
29
Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
30
School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
31
School of Medicine, National Yang-Ming University, Taipei, Taiwan.
32
School of Medicine, National Defense Medical Center, Taipei, Taiwan.
33
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
34
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
35
Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Osaka, Japan.
36
CHU de Poitiers, Centre d'Investigation Clinique, Poitiers, France.
37
Université de Poitiers, UFR Médecine Pharmacie, Centre d'Investigation Clinique 1402, Poitiers, France.
38
INSERM, Centre d'Investigation Clinique 1402, Poitiers, France.
39
L'Institut du Thorax, INSERM, CNRS, CHU Nantes, Nantes, France.
40
Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
41
Department of Diabetology, Endocrinology and Nutrition, Assistance Publique-Hôpitaux de Paris, Bichat Hospital, DHU FIRE, Paris, France.
42
INSERM U1138, Centre de Recherche des Cordeliers, Paris, France.
43
Team Genomics & Pathophysiology of Cardiovascular Diseases, UPMC, Sorbonne Universités, INSERM, UMR_S 1166, Paris, France.
44
Institute of Cardiometabolism and Nutrition, Paris, France.
45
Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA.
46
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, U.K.
47
Wellcome Centre for Human Genetics, University of Oxford, Oxford, U.K.
48
NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
49
Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden.
50
Department of Clinical Science, KG Jebsen Center for Diabetes Research, University of Bergen, Bergen, Norway.
51
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, U.K.
52
Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K.
53
Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, U.K.
54
Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
55
Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
56
Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
57
Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
58
Department of Preventive Medicine, John D. Bower School of Population Health, University of Mississippi Medical Center, Jackson, MS.
59
Department of Ophthalmology, University of Mississippi Medical Center, Jackson, MS.
60
Centre for Vision Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
61
Department of Ophthalmology, Flinders University, Bedford Park, South Australia, Australia.
62
Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, MD.
63
Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
64
Program in Genetics & Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
65
Epidemiology and Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
66
Grassi Retina, Naperville, IL.
67
Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL.
68
Pat MacPherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K.
69
Genentech, Inc., South San Francisco, CA.
70
Institute for Urban Health, New York Academy of Medicine, New York, NY.
71
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
72
Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
73
Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI.
74
Massachusetts Eye and Ear Department of Ophthalmology, Harvard Medical School, Boston, MA lucia_sobrin@meei.harvard.edu.

Abstract

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value <1 × 10-5 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like (NVL) was associated with DR in European discovery cohorts (P = 2.1 × 10-9), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity (P = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in NVL, as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.

PMID:
30487263
PMCID:
PMC6341299
[Available on 2020-02-01]
DOI:
10.2337/db18-0567
[Indexed for MEDLINE]
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