Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control-Reference-Cited by-同舟云学术

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

Published:2018-11-28 Issue:2 Volume:68 Page:441-456
ISSN:0012-1797
Container-title:Diabetes
language:en
Short-container-title:

Author:

Pollack Samuela¹,Igo Robert P.²,Jensen Richard A.³,Christiansen Mark³,Li Xiaohui⁴,Cheng Ching-Yu⁵⁶^ORCID,Ng Maggie C.Y.⁷⁸,Smith Albert V.⁹,Rossin Elizabeth J.¹⁰,Segrè Ayellet V.¹⁰,Davoudi Samaneh¹⁰,Tan Gavin S.⁵⁶,Chen Yii-Der Ida⁴,Kuo Jane Z.⁴¹¹,Dimitrov Latchezar M.⁷⁸,Stanwyck Lynn K.¹⁰,Meng Weihua¹²,Hosseini S. Mohsen¹³,Imamura Minako¹⁴¹⁵¹⁶,Nousome Darryl¹⁷,Kim Jihye¹⁸,Hai Yang⁴,Jia Yucheng⁴,Ahn Jeeyun¹⁹,Leong Aaron²⁰,Shah Kaanan²¹,Park Kyu Hyung²²,Guo Xiuqing⁴,Ipp Eli²³^ORCID,Taylor Kent D.⁴,Adler Sharon G.²⁴,Sedor John R.²⁵²⁶²⁷,Freedman Barry I.²⁸^ORCID,Lee I-Te²⁹³⁰³¹^ORCID,Sheu Wayne H.-H.²⁹³⁰³¹³²,Kubo Michiaki³³,Takahashi Atsushi³⁴³⁵,Hadjadj Samy³⁶³⁷³⁸³⁹^ORCID,Marre Michel⁴⁰⁴¹⁴²,Tregouet David-Alexandre⁴³⁴⁴,Mckean-Cowdin Roberta¹⁷⁴⁵,Varma Rohit¹⁷⁴⁵,McCarthy Mark I.⁴⁶⁴⁷⁴⁸,Groop Leif⁴⁹,Ahlqvist Emma⁴⁹,Lyssenko Valeriya⁴⁹⁵⁰,Agardh Elisabet⁴⁹,Morris Andrew⁵¹,Doney Alex S.F.⁵²,Colhoun Helen M.⁵³^ORCID,Toppila Iiro⁵⁴⁵⁵⁵⁶,Sandholm Niina⁵⁴⁵⁵⁵⁶^ORCID,Groop Per-Henrik⁵⁴⁵⁵⁵⁶⁵⁷^ORCID,Maeda Shiro¹⁴¹⁵¹⁶^ORCID,Hanis Craig L.¹⁸^ORCID,Penman Alan⁵⁸,Chen Ching J.⁵⁹,Hancock Heather⁵⁹,Mitchell Paul⁶⁰,Craig Jamie E.⁶¹,Chew Emily Y.⁶²,Paterson Andrew D.⁶³⁶⁴⁶⁵^ORCID,Grassi Michael A.⁶⁶⁶⁷,Palmer Colin⁶⁸,Bowden Donald W.⁷⁸,Yaspan Brian L.⁶⁹,Siscovick David⁷⁰,Cotch Mary Frances⁶²,Wang Jie Jin⁵⁶⁰,Burdon Kathryn P.⁷¹,Wong Tien Y.⁵⁷²,Klein Barbara E.K.⁷³^ORCID,Klein Ronald⁷³^ORCID,Rotter Jerome I.⁴,Iyengar Sudha K.²,Price Alkes L.¹,Sobrin Lucia¹⁰^ORCID,

Affiliation:

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

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.

Funder

Research to Prevent Blindness, Inc.

National Eye Institute

Massachusetts Lions Eye Research Fund

Alcon Research Institute

American Diabetes Association

Harvard Catalyst

National Institute on Aging

NIH

National Heart, Lung, and Blood Institute

National Human Genome Research Institute

National Health and Medical Research Council