Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci-Reference-Cited by-同舟云学术

Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Published:2016-07-14 Issue:10 Volume:65 Page:3200-3211
ISSN:0012-1797
Container-title:Diabetes
language:en
Short-container-title:

Author:

Walford Geoffrey A.¹²³,Gustafsson Stefan⁴,Rybin Denis⁵,Stančáková Alena⁶,Chen Han⁷⁸,Liu Ching-Ti⁷,Hong Jaeyoung⁷,Jensen Richard A.⁹¹⁰,Rice Ken¹¹,Morris Andrew P.¹²¹³,Mägi Reedik¹⁴,Tönjes Anke¹⁵,Prokopenko Inga¹³¹⁶¹⁷,Kleber Marcus E.¹⁸,Delgado Graciela¹⁸,Silbernagel Günther¹⁹,Jackson Anne U.²⁰,Appel Emil V.²¹,Grarup Niels²¹,Lewis Joshua P.²²²³,Montasser May E.²²²³,Landenvall Claes²⁴²⁵,Staiger Harald²⁶²⁷²⁸,Luan Jian’an²⁹,Frayling Timothy M.³⁰,Weedon Michael N.³⁰,Xie Weijia³⁰,Morcillo Sonsoles³¹³²,Martínez-Larrad María Teresa³³,Biggs Mary L.⁹¹¹,Chen Yii-Der Ida³⁴,Corbaton-Anchuelo Arturo³³,Færch Kristine³⁵,Gómez-Zumaquero Juan Miguel³⁶³⁷,Goodarzi Mark O.³⁸,Kizer Jorge R.³⁹⁴⁰,Koistinen Heikki A.⁴¹⁴²⁴³,Leong Aaron³⁴⁴,Lind Lars⁴,Lindgren Cecilia¹³⁴⁵,Machicao Fausto²⁷²⁸,Manning Alisa K.²³⁴⁵,Martín-Núñez Gracia María⁴⁶,Rojo-Martínez Gemma³²³⁶⁴⁷,Rotter Jerome I.³⁴,Siscovick David S.⁹¹⁰⁴⁸⁴⁹,Zmuda Joseph M.⁵⁰,Zhang Zhongyang⁵¹⁵²,Serrano-Rios Manuel³³,Smith Ulf⁵³,Soriguer Federico³²³⁶⁴⁷,Hansen Torben²¹,Jørgensen Torben J.⁵⁴⁵⁵⁵⁶,Linnenberg Allan⁵⁶⁵⁷⁵⁸,Pedersen Oluf²¹,Walker Mark⁵⁹,Langenberg Claudia²⁹,Scott Robert A.²⁹,Wareham Nicholas J.²⁹,Fritsche Andreas²⁶²⁷²⁸,Häring Hans-Ulrich²⁶²⁷²⁸,Stefan Norbert²⁶²⁷²⁸,Groop Leif²⁴⁶⁰,O’Connell Jeff R.²²²³,Boehnke Michael²⁰,Bergman Richard N.⁶¹,Collins Francis S.⁶²,Mohlke Karen L.⁶³,Tuomilehto Jaakko⁶⁴⁶⁵⁶⁶⁶⁷,März Winfried¹⁸⁶⁸⁶⁹,Kovacs Peter⁷⁰,Stumvoll Michael¹⁵,Psaty Bruce M.⁹¹⁰⁷¹⁷²⁷³,Kuusisto Johanna⁷⁴,Laakso Markku⁷⁴,Meigs James B.³⁴⁴⁴⁵,Dupuis Josée⁷⁷⁵,Ingelsson Erik⁷⁶⁷⁷,Florez Jose C.¹²³

Affiliation:

1. Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA

2. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA

3. Department of Medicine, Harvard Medical School, Boston, MA

4. Department of Medical Sciences, Uppsala University, Uppsala, Sweden

5. Data Coordinating Center, Boston University School of Public Health, Boston, MA

6. University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland

7. Department of Biostatistics, Boston University School of Public Health, Boston, MA

8. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA

9. Cardiovascular Health Research Unit, University of Washington, Seattle, WA

10. Department of Medicine, University of Washington, Seattle, WA

11. Department of Biostatistics, University of Washington, Seattle, WA

12. Department of Biostatistics, University of Liverpool, Liverpool, U.K.

13. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.

14. Estonian Genome Center, University of Tartu, Tartu, Estonia

15. Department of Medicine, University of Leipzig, Leipzig, Germany

16. Department of Genomics of Common Disease, Imperial College London, London, U.K.

17. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.

18. Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany

19. Division of Angiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

20. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI

21. The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

22. Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD

23. Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD

24. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden

25. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

26. Department of Internal Medicine, Division of Endocrinology and Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany

27. German Center for Diabetes Research (DZD), Tübingen, Germany

28. Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany

29. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.

30. University of Exeter Medical School, Exeter, U.K.

31. CIBER Pathophysiology of Obesity and Nutrition, Madrid, Spain

32. Department of Endocrinology and Nutrition, Hospital Regional Universitario de Málaga, Málaga, Spain

33. Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain

34. Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA

35. Steno Diabetes Center, Gentofte, Denmark

36. Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain

37. Sequencing and Genotyping Platform, Hospital Carlos Haya de Málaga, Málaga, Spain

38. Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA

39. Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY

40. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY

41. Department of Health, National Institute for Health and Welfare, Helsinki, Finland

42. Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki, Finland

43. Department of Medicine and Abdominal Center: Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

44. Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA

45. Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA

46. Department of Endocrinology and Nutrition, Hospitales Regional Universitario y Virgen de la Victoria de Málaga, Málaga, Spain

47. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain

48. Department of Epidemiology, University of Washington, Seattle, WA

49. The New York Academy of Medicine, New York, NY

50. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA

51. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY

52. Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY

53. The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

54. Department of Public Health, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark

55. Faculty of Medicine, Aalborg University, Aalborg, Denmark

56. Research Center for Prevention and Health, The Capital Region of Denmark, Copenhagen, Denmark

57. Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark

58. Department of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark

59. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K.

60. Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland

61. Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA

62. Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

63. Department of Genetics, University of North Carolina, Chapel Hill, NC

64. Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland

65. Centre for Vascular Prevention, Danube-University Krems, Krems, Austria

66. Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia

67. Dasman Diabetes Institute, Dasman, Kuwait

68. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria

69. Synlab Academy, Synlab Services GmbH, Mannheim and Augsburg, Germany

70. Integrated Research and Treatment (IFB) Center AdiposityDiseases, University of Leipzig, Leipzig, Germany

71. Epidemiology and Health Services, University of Washington, Seattle, WA

72. Group Health Research Institute, Seattle, WA

73. Group Health Cooperation, Seattle, WA

74. Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland

75. Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA

76. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden

77. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA

Abstract

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10−11), rs12454712 (BCL2; P = 2.7 × 10−8), and rs10506418 (FAM19A2; P = 1.9 × 10−8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

Funder

Academy of Finland

German Research Council

Diabetes Hilfs- und Forschungsfonds Deutschland (DHFD)

Federal Ministry of Education and Research (BMBF), Germany, FKZ

National Heart, Lung, and Blood Institute

National Institute of Diabetes and Digestive and Kidney Diseases

American Diabetes Association Research Association

Swedish Diabetes Foundation

Swedish Research Council

Swedish Heart-Lung Foundation

Wellcome Trust