Preprint open access publication

Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation

bioRxiv, Cold Spring Harbor Laboratory,

2019

DOI:10.1101/790618, Dimensions: pub.1121495771,

Authors

Fine, Rebecca S. (5) (6) (7)
Wessel, Jennifer (9) (10)
Sim, Xueling (11) (12)
Chen, Sai (12)
An, Ping (25)
Auvinen, Juha (27) (28)
Li, Jin (37)
Li, Man (26) (38)
Lu, Yingchang (40) (41)
Marzi, Carola (43) (44)
Meidtner, Karina (43) (45)
Muka, Taulant (32) (46)
Pistis, Giorgio (12) (47)
Sanna, Serena (47) (48)
Shi, Yuan (49)
Southam, Lorraine (4) (8) (44)
Yao, Jie (16)
Zhang, Weihua (35) (55)
Zhao, Wei (12)
Alhejily, Wesam A (36) (60)
Asselbergs, Folkert W. (52) (61) (62)
Chen, Ji (8)
Dehghan, Abbas (32) (35) (67)
Elliott, Paul (35) (68) (69)
Franks, Paul W. (5) (7) (19)
Fritsche, Andreas (43) (71)
Herzig, Karl-Heinz (28) (74)
Jhun, Min A (12) (75)
Jørgensen, Torben (18) (76) (77)
Kajantie, Eero (27) (79) (80) (81)
Koistinen, Heikki A. (79) (83) (84)
Launer, Lenore J. (34) (79)
Mulas, Antonella (47) (93)
Nalls, Mike A. (51) (94)
Renström, Frida (19) (73)
Roden, Michael (43) (99) (100)
Saleheen, Danish (89) (98)
Savonen, Kai (85) (92)
Tai, E-Shyong (11) (103)
Tuomi, Tiinamaija (84) (105) (106)
Tuomilehto, Jaakko (60) (79) (106) (107)
Chambers, John C (35) (55) (109)
Chasman, Daniel I (7) (31) (110)
Cheng, Ching-Yu (11) (49) (103)
Cucca, Francesco (47) (93)
Deloukas, Panos (36) (60)
Dupuis, Josée (15) (111)
Franco, Oscar H (32) (46)
Grallert, Harald (43) (44)
Groop, Leif (19) (106)
Hansen, Torben (18) (78)
Hirschhorn, Joel N. (5) (6) (113)
Ingelsson, Erik (33) (37)
Karpe, Fredrik (2) (114)
Kooner, Jaspal S (35) (55) (109)
Lakka, Timo (85) (87) (92)
Lind, Lars (33)
Linneberg, Allan (18) (77)
Liu, Jun (32)
Psaty, Bruce M (29) (118)
Ridker, Paul M (7) (31) (119)
Rorsman, Patrik (2) (114)
Walker, Mark (121)
Wong, Tien Yin (11) (49) (103)
Morris, Andrew P. (4) (123)
Florez, Jose (6) (124)
McCarthy, Mark I (2) (4) (114)
Meigs, James B (6) (90)
Gloyn, Anna L * (2) (4) (114)
Barroso, Inês * (3) (8)

* Corresponding author

Affiliations

Organisations

  1. (1) Institute of Molecular and Cell Biology, grid.418812.6
  2. (2) University of Oxford, grid.4991.5
  3. (3) Institute of Metabolic Science, grid.470900.a
  4. (4) Wellcome Centre for Human Genetics, grid.270683.8
  5. (5) Boston Children's Hospital, grid.2515.3
  6. (6) Broad Institute, grid.66859.34
  7. (7) Harvard University, grid.38142.3c
  8. (8) Wellcome Sanger Institute, grid.10306.34
  9. (9) Departments of Epidemiology & Medicine, Schools of Public Health & Medicine, Indiana University, Indiaiapolis, IN 46202
  10. (10) Indiana University – Purdue University Indianapolis, grid.257413.6
  11. (11) National University of Singapore, grid.4280.e
  12. (12) University of Michigan, grid.214458.e
  13. (13) University of Exeter, grid.8391.3
  14. (14) Vertex Pharmaceuticals Europe Ltd, Milton Park, Abingdon, OX14 4RW, UK
  15. (15) Boston University, grid.189504.1
  16. (16) Harbor–UCLA Medical Center, grid.239844.0
  17. (17) Leiden University Medical Center, grid.10419.3d
  18. (18) University of Copenhagen, grid.5254.6, KU
  19. (19) Lund University, grid.4514.4
  20. (20) MRC Biostatistics Unit, grid.415038.b
  21. (21) Karolinska Institute, grid.4714.6
  22. (22) University of Glasgow, grid.8756.c
  23. (23) Wayne State University, grid.254444.7
  24. (24) Steno Diabetes Center, grid.419658.7, Capital Region
  25. (25) Washington University in St. Louis, grid.4367.6
  26. (26) Johns Hopkins University, grid.21107.35
  27. (27) University of Oulu, grid.10858.34
  28. (28) Oulu University Hospital, grid.412326.0
  29. (29) University of Washington, grid.34477.33
  30. (30) University of Edinburgh, grid.4305.2
  31. (31) Brigham and Women's Hospital, grid.62560.37
  32. (32) Erasmus University Medical Center, grid.5645.2
  33. (33) Uppsala University, grid.8993.b
  34. (34) Icelandic Heart Association, grid.420802.c
  35. (35) Imperial College London, grid.7445.2
  36. (36) Queen Mary University of London, grid.4868.2
  37. (37) Stanford University, grid.168010.e
  38. (38) University of Utah, grid.223827.e
  39. (39) Wake Forest University, grid.241167.7
  40. (40) Department of Medicine, Division of Epidemiology, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine Nashville, TN 37203, USA
  41. (41) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  42. (42) Massachusetts General Hospital, grid.32224.35
  43. (43) German Center for Diabetes Research, grid.452622.5
  44. (44) Helmholtz Zentrum München, grid.4567.0
  45. (45) German Institute of Human Nutrition, grid.418213.d
  46. (46) University of Bern, grid.5734.5
  47. (47) Italian National Research Council, Institute of Genetics and Biomedic Research, Cittadella Universitaria, Monserrato (CA) 09042, Italy
  48. (48) University Medical Center Groningen, grid.4494.d
  49. (49) Singapore National Eye Center, grid.419272.b
  50. (50) University of Iceland, grid.14013.37
  51. (51) National Institute on Aging, grid.419475.a
  52. (52) Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3584CX Utrecht, The Netherlands
  53. (53) University Medical Center Utrecht, grid.7692.a
  54. (54) Brunel University London, grid.7728.a
  55. (55) Ealing Hospital, grid.415918.0
  56. (56) Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Skåne University Hospital, SE-20502 Malmö, Sweden
  57. (57) University of North Carolina at Chapel Hill, grid.10698.36
  58. (58) The University of Texas Health Science Center at Houston, grid.267308.8
  59. (59) Montreal Heart Institute, Université de Montréal, Montreal, Quebec, H1T 1C8, Canada
  60. (60) King Abdulaziz University, grid.412125.1
  61. (61) Netherlands Heart Institute, grid.411737.7
  62. (62) University College London, grid.83440.3b
  63. (63) National Human Genome Research Institute, grid.280128.1
  64. (64) Department of Clinical Biochemistry, Lillebaelt Hospital Vejle, 7100 Vejle, Denmark
  65. (65) Medical Department, Lillebaelt Hospital Vejle, 7100 Vejle, Denmark
  66. (66) University of Cambridge, grid.5335.0
  67. (67) Department of Biostatistics and Epidemiology, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London
  68. (68) Health Data Research UK – London at Imperial College London, United Kingdom
  69. (69) National Institute for Health Research, grid.451056.3
  70. (70) Harokopio University, grid.15823.3d
  71. (71) Universitätsklinikum Tübingen, grid.411544.1
  72. (72) Cedars-Sinai Medical Center, grid.50956.3f
  73. (73) Umeå University, grid.12650.30
  74. (74) Poznan University of Medical Sciences, grid.22254.33
  75. (75) Fred Hutchinson Cancer Research Center, grid.270240.3
  76. (76) Aalborg University, grid.5117.2, AAU
  77. (77) Bispebjerg Hospital, grid.411702.1, Capital Region
  78. (78) University of Southern Denmark, grid.10825.3e, SDU
  79. (79) National Institute for Health and Welfare, grid.14758.3f
  80. (80) Children’s Hospital, Helsinki University Hospital and University of Helsinki
  81. (81) Norwegian University of Science and Technology, grid.5947.f
  82. (82) Echinos Medical Centre, Echinos, Greece
  83. (83) Minerva Foundation, grid.452540.2
  84. (84) Helsinki University Central Hospital, grid.15485.3d
  85. (85) Kuopion Liikuntalääketieteen Tutkimuslaitos, grid.419013.e
  86. (86) Leipzig University, grid.9647.c
  87. (87) University of Eastern Finland, grid.9668.1
  88. (88) University of Colorado Anschutz Medical Campus, grid.430503.1
  89. (89) Department of Biostatistics and Epidemiology, University of Pennsylvania, USA, 19104
  90. (90) Division of General Internal Medicine, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, MA, USA
  91. (91) University of Alberta, grid.17089.37
  92. (92) Kuopio University Hospital, grid.410705.7
  93. (93) University of Sassari, grid.11450.31
  94. (94) Data Tecnica International, LLC, Glen Echo, Maryland 20812, USA
  95. (95) University of Minnesota, grid.17635.36
  96. (96) Odense University Hospital, grid.7143.1, Southern Denmark Region
  97. (97) South Ostobothnia Central Hospital, 60220 Seinajoki, Finland
  98. (98) Center for Non-Communicable Diseases, grid.497620.e
  99. (99) Düsseldorf University Hospital, grid.14778.3d
  100. (100) German Diabetes Center - Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, grid.429051.b
  101. (101) Central Finland Health Care District, grid.460356.2
  102. (102) King's College London, grid.13097.3c
  103. (103) Duke NUS Graduate Medical School, grid.428397.3
  104. (104) Anogia Medical Centre, Anogia, Greece
  105. (105) Folkhälsans Forskningscentrum, grid.428673.c
  106. (106) University of Helsinki, grid.7737.4
  107. (107) Danube University Krems, grid.15462.34
  108. (108) Centre for research in epidemiology and population health, grid.463845.8
  109. (109) Imperial College Healthcare NHS Trust, grid.417895.6
  110. (110) Division of Genetics, Brigham and Women’s Hospital and Harvard Medical School, Boston MA, USA
  111. (111) National Heart Lung and Blood Institute, grid.279885.9
  112. (112) Istituto di Fisiologia Clinica, grid.418529.3
  113. (113) Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA 02115
  114. (114) Churchill Hospital, grid.415719.f
  115. (115) University of Aberdeen, grid.7107.1
  116. (116) University of Dundee, grid.8241.f
  117. (117) University of Split, grid.38603.3e
  118. (118) Kaiser Permanent Washington Health Research Institute, Seattle, WA, USA
  119. (119) Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston MA 02115
  120. (120) McGill University, grid.14709.3b
  121. (121) Newcastle University, grid.1006.7
  122. (122) University of Mississippi Medical Center, grid.410721.1
  123. (123) University of Liverpool, grid.10025.36
  124. (124) Diabetes Unit, Department of Medicine, Massachusetts General, Boston, MA, USA

Description

Summary Metabolic dysregulation in multiple tissues alters glucose homeostasis and influences risk for type 2 diabetes (T2D). To identify pathways and tissues influencing T2D-relevant glycemic traits (fasting glucose [FG], fasting insulin [FI], two-hour glucose [2hGlu] and glycated hemoglobin [HbA1c]), we investigated associations of exome-array variants in up to 144,060 individuals without diabetes of multiple ancestries. Single-variant analyses identified novel associations at 21 coding variants in 18 novel loci, whilst gene-based tests revealed signals at two genes, TF (HbA1c) and G6PC (FG, FI). Pathway and tissue enrichment analyses of trait-associated transcripts confirmed the importance of liver and kidney for FI and pancreatic islets for FG regulation, implicated adipose tissue in FI and the gut in 2hGlu, and suggested a role for the non-endocrine pancreas in glucose homeostasis. Functional studies demonstrated that a novel FG/FI association at the liver-enriched G6PC transcript was driven by multiple rare loss-of-function variants. The FG/HbA1c-associated, islet-specific G6PC2 transcript also contained multiple rare functional variants, including two alleles within the same codon with divergent effects on glucose levels. Our findings highlight the value of integrating genomic and functional data to maximize biological inference. Highlights 23 novel coding variant associations (single-point and gene-based) for glycemic traits 51 effector transcripts highlighted different pathway/tissue signatures for each trait The exocrine pancreas and gut influence fasting and 2h glucose, respectively Multiple variants in liver-enriched G6PC and islet-specific G6PC2 influence glycemia

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