Article open access publication

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

American Journal of Human Genetics, Elsevier, ISSN 1537-6605

Volume 103, 5, 2018

DOI:10.1016/j.ajhg.2018.09.009, Dimensions: pub.1107947593, PMC: PMC6218410, PMID: 30388399,

Authors

Vaez, Ahmad (2) (3)
Võsa, Urmo (3) (4)
Wu, Ying (10)
Pool, René (14) (15)
Zhu, Gu (16)
Macé, Aurélien (17) (18) (19)
Mangino, Massimo (22) (23)
Kemp, John P. (25) (26)
Abbasi, Ali (3) (27)
Kacprowski, Tim (28) (29)
Smith, Albert V. (30) (31)
Huang, Tao (32) (33)
Marzi, Carola (34) (35)
Mueller, Christian (28) (40) (41)
Deelen, Joris (21) (46)
Lahti, Jari (42) (50)
Bak, Tom (57)
Schork, Nicholas (58) (59)
Zhang, Weihua (65) (66)
Ang, Wei (70)
Yengo, Loic (25) (72)
Zhao, Jing (78)
Draisma, Harmen H M (14) (15) (79)
Ford, Ian (80)
Wahl, Simone (34) (35)
Huang, Jie (81)
Laakso, Markku (85) (86)
Rueedi, Rico (17) (18)
Herzig, Karl-Heinz (89) (90)
Frånberg, Mattias (11) (91)
St Pourcain, Beate (26) (92)
Felix, Stephan B. (28) (29)
Pers, Tune H. (49) (93)
Ruggiero, Daniela (55) (96)
Tiesler, Carla M T (61) (62)
Wang, Yunmei (100)
Lorentzon, Matthias (67) (101)
Beilby, John (70) (102)
Musk, A.W. (95)
Evans, David M (25) (26)
Kähönen, Mika (43) (105)
Kutalik, Zoltán (18) (19)
Raitakari, Olli T. (109) (110)
Attia, John R. (44) (45) (111)
Kajantie, Eero (42) (47) (90)
Lindgren, Cecilia M. (63) (107) (113)
Lind, Lars (99)
Li, Jun Z. (64)
Chambers, John C. (65) (66) (115) (116)
Auvinen, Juha (90) (117)
Meitinger, Thomas (119) (120) (121)
McEvoy, Mark (44) (45)
Ridker, Paul M (9) (33)
Jarvelin, Marjo-Riitta (66) (90) (117) (124)
Jukema, J. Wouter (21) (125) (126)
Zeller, Tanja (28) (41)
Nauck, Matthias (28) (29)
Qi, Lu (33) (98)
Grallert, Harald (34) (35)
März, Winfried (38) (75) (128)
Wild, Philipp S. (28) (94)
Melbye, Mads (49) (93) (129)
Ciullo, Marina (55) (96)
Pramstaller, Peter P. (60) (133) (134)
Heinrich, Joachim (61) (136)
Ingelsson, Erik (99) (129)
Kooner, Jaspal S. (65) (66) (116)
Froguel, Philippe (66) (72)
Jess, Tine (139)
Franco, Oscar H. (1) (141)
Benjamin, Emelia J (13) (142)
Dehghan, Abbas * (1) (66)
Gross, Myron (145)
Wilson, James F (51) (137)
Psaty, Bruce M (140) (146)
Dupuis, Josée (142) (147)
Koenig, Wolfgang (28) (121) (148)
Boerwinkle, Eric (6) (88)
Morris, Andrew P. (63) (149)
Eriksson, Johan G. (47) (50) (150)

* Corresponding author

Affiliations

Organisations

  1. (1) Erasmus University Medical Center, grid.5645.2
  2. (2) Isfahan University of Medical Sciences, grid.411036.1
  3. (3) University Medical Center Groningen, grid.4494.d
  4. (4) University of Tartu, grid.10939.32
  5. (5) University of Lorraine, grid.29172.3f
  6. (6) The University of Texas Health Science Center at Houston, grid.267308.8
  7. (7) Wellcome Sanger Institute, grid.10306.34
  8. (8) National Institute on Aging, grid.419475.a
  9. (9) Brigham and Women's Hospital, grid.62560.37
  10. (10) University of North Carolina at Chapel Hill, grid.10698.36
  11. (11) Karolinska Institute, grid.4714.6
  12. (12) University of Split, grid.38603.3e
  13. (13) Boston University School of Medicine, grid.475010.7
  14. (14) VU Amsterdam, grid.12380.38
  15. (15) VU University Medical Center, grid.16872.3a
  16. (16) QIMR Berghofer Medical Research Institute, grid.1049.c
  17. (17) University of Lausanne, grid.9851.5
  18. (18) Swiss Institute of Bioinformatics, grid.419765.8
  19. (19) Institute of Social and Preventive Medicine, grid.482968.9
  20. (20) Institute of Genetic and Biomedical Research, grid.428485.7
  21. (21) Leiden University Medical Center, grid.10419.3d
  22. (22) Guy's and St Thomas' NHS Foundation Trust, grid.420545.2
  23. (23) King's College London, grid.13097.3c
  24. (24) Unit of Genomics of Complex Diseases, Institut d’Investigació Biomèdica Sant Pau, Barcelona 08025, Spain
  25. (25) University of Queensland, grid.1003.2
  26. (26) University of Bristol, grid.5337.2
  27. (27) MRC Epidemiology Unit, University of Cambridge School of Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
  28. (28) German Centre for Cardiovascular Research, grid.452396.f
  29. (29) University of Greifswald, grid.5603.0
  30. (30) University of Iceland, grid.14013.37
  31. (31) Icelandic Heart Association, grid.420802.c
  32. (32) Peking University, grid.11135.37
  33. (33) Harvard University, grid.38142.3c
  34. (34) Helmholtz Zentrum München, grid.4567.0
  35. (35) German Center for Diabetes Research, grid.452622.5
  36. (36) Washington University in St. Louis, grid.4367.6
  37. (37) Wake Forest Baptist Medical Center, grid.412860.9
  38. (38) Heidelberg University, grid.7700.0
  39. (39) Department of Psychiatry, Amsterdam Neuroscience and Amsterdam Public Health Research Institute, Amsterdam University Medical Center/GGZ inGeest Research Innovation, Amsterdam 1081 HJ, the Netherlands
  40. (40) University Hospital Schleswig-Holstein, grid.412468.d
  41. (41) University Medical Center Hamburg-Eppendorf, grid.13648.38
  42. (42) University of Helsinki, grid.7737.4
  43. (43) Tampere University, grid.502801.e
  44. (44) Hunter Medical Research Institute, grid.413648.c
  45. (45) University of Newcastle Australia, grid.266842.c
  46. (46) Max Planck Institute for Biology of Ageing, grid.419502.b
  47. (47) National Institute for Health and Welfare, grid.14758.3f
  48. (48) Institute of Metabolic Science, grid.470900.a
  49. (49) State Serum Institute, grid.6203.7
  50. (50) Folkhälsans Forskningscentrum, grid.428673.c
  51. (51) University of Edinburgh, grid.4305.2
  52. (52) Mahidol University, grid.10223.32
  53. (53) University of Virginia, grid.27755.32
  54. (54) Los Angeles Biomedical Research Institute, grid.279946.7
  55. (55) Institute of Genetics and Biophysics “A. Buzzati-Traverso,” Consiglio Nazionale delle Ricerche, Napoli 80131, Italy
  56. (56) University of Verona, grid.5611.3
  57. (57) Interdisciplinary Center Psychopathology and Emotion regulation, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, the Netherlands
  58. (58) J. Craig Venter Institute, grid.469946.0
  59. (59) Translational Genomics Research Institute, grid.250942.8
  60. (60) Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano 39100, Italy
  61. (61) Friedrich Loeffler Institute, grid.417834.d
  62. (62) Ludwig Maximilian University of Munich, grid.5252.0
  63. (63) Wellcome Centre for Human Genetics, grid.270683.8
  64. (64) University of Michigan, grid.214458.e
  65. (65) Ealing Hospital, grid.415918.0
  66. (66) Imperial College London, grid.7445.2
  67. (67) University of Gothenburg, grid.8761.8
  68. (68) University of Maryland, Baltimore, grid.411024.2
  69. (69) University of Alabama at Birmingham, grid.265892.2
  70. (70) University of Western Australia, grid.1012.2
  71. (71) AREA Science Park, grid.419994.8
  72. (72) Pasteur Institute of Lille, grid.8970.6
  73. (73) National Research Council, grid.5326.2
  74. (74) Fred Hutchinson Cancer Research Center, grid.270240.3
  75. (75) Medical University of Graz, grid.11598.34
  76. (76) Rush University Medical Center, grid.240684.c
  77. (77) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  78. (78) Georgia Institute of Technology, grid.213917.f
  79. (79) Amsterdam Neuroscience, grid.484519.5
  80. (80) University of Glasgow, grid.8756.c
  81. (81) Boston VA Research Institute, grid.417499.6
  82. (82) Johns Hopkins University, grid.21107.35
  83. (83) Institute for Maternal and Child Health, IRCCS “Burlo Garofolo,” Trieste 34140, Italy
  84. (84) Istituto di Genetica Molecolare, grid.419479.6
  85. (85) Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio 70210, Finland
  86. (86) Kuopio University Hospital, grid.410705.7
  87. (87) Houston Methodist, grid.63368.38
  88. (88) Baylor College of Medicine, grid.39382.33
  89. (89) Poznan University of Medical Sciences, grid.22254.33
  90. (90) University of Oulu, grid.10858.34
  91. (91) Stockholm University, grid.10548.38
  92. (92) Radboud University Nijmegen, grid.5590.9
  93. (93) University of Copenhagen, grid.5254.6, KU
  94. (94) University Medical Center of the Johannes Gutenberg University Mainz, grid.410607.4
  95. (95) Sir Charles Gairdner Hospital, grid.3521.5
  96. (96) Istituto Neurologico Mediterraneo, grid.419543.e
  97. (97) University of California, San Diego, grid.266100.3
  98. (98) Tulane University, grid.265219.b
  99. (99) Uppsala University, grid.8993.b
  100. (100) Case Western Reserve University, grid.67105.35
  101. (101) Sahlgrenska University Hospital, grid.1649.a
  102. (102) Pathwest Laboratory Medicine, grid.2824.c
  103. (103) University of Trieste, grid.5133.4
  104. (104) Centre for research in epidemiology and population health, grid.463845.8
  105. (105) Tampere University Hospital, grid.412330.7
  106. (106) BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow G12 8TA, UK
  107. (107) University of Oxford, grid.4991.5
  108. (108) National Institutes of Health, grid.94365.3d
  109. (109) Turku University Hospital, grid.410552.7
  110. (110) University of Turku, grid.1374.1
  111. (111) John Hunter Hospital, grid.414724.0
  112. (112) Catholic University of the Sacred Heart, grid.8142.f
  113. (113) Broad Institute, grid.66859.34
  114. (114) Lund University, grid.4514.4
  115. (115) Nanyang Technological University, grid.59025.3b
  116. (116) Imperial College Healthcare NHS Trust, grid.417895.6
  117. (117) Oulu University Hospital, grid.412326.0
  118. (118) University College Cork, grid.7872.a
  119. (119) Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany
  120. (120) Munich Cluster for Systems Neurology, grid.452617.3
  121. (121) Technical University of Munich, grid.6936.a
  122. (122) Population Health Research Institute, St. George’s, University of London, London SW17 0RE, UK
  123. (123) University Hospital of Lausanne, grid.8515.9
  124. (124) Brunel University London, grid.7728.a
  125. (125) Durrer Center for Cardiogenetic Research, Amsterdam 3501 DG, the Netherlands
  126. (126) Netherlands Heart Institute, grid.411737.7
  127. (127) Regeneron (United States), grid.418961.3
  128. (128) Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim 68161, Germany
  129. (129) Stanford University, grid.168010.e
  130. (130) UCSF Benioff Children's Hospital, grid.414016.6
  131. (131) Azienda Ospedaliera Universitaria Integrata Verona, grid.411475.2
  132. (132) University of Adelaide, grid.1010.0
  133. (133) General Central Hospital, Department of Neurology, Bolzano 39100, Italy
  134. (134) University of Lübeck, grid.4562.5
  135. (135) Azienda Sanitaria di Firenze, grid.423864.f
  136. (136) Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich, Member DZL, German Center for Lung Research, 81377 Munich, Germany
  137. (137) MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
  138. (138) University of Kentucky, grid.266539.d
  139. (139) Bispebjerg Hospital, grid.411702.1, Capital Region
  140. (140) University of Washington, grid.34477.33
  141. (141) University of Bern, grid.5734.5
  142. (142) National Heart Lung and Blood Institute, grid.279885.9
  143. (143) Steno Diabetes Center, grid.419658.7, Capital Region
  144. (144) University of Vermont, grid.59062.38
  145. (145) University of Minnesota, grid.17635.36
  146. (146) Kaiser Permanente Washington Health Research Institute, grid.488833.c
  147. (147) Boston University, grid.189504.1
  148. (148) University Hospital Ulm, grid.410712.1
  149. (149) University of Liverpool, grid.10025.36
  150. (150) Helsinki University Central Hospital, grid.15485.3d

Description

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

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University of Copenhagen

Danish Open Access Indicator

2018: Realized

Research area: Medicine

Danish Bibliometrics Indicator

2018: Level 2

Research area: Medicine

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Times Cited: 52

Field Citation Ratio (FCR): 17

Relative Citation ratio (RCR): 3.51

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Hybrid