Article open access publication

Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

American Journal of Epidemiology, Oxford University Press (OUP), ISSN 1476-6256

Volume 188, 6, 2019

DOI:10.1093/aje/kwz005, Dimensions: pub.1111458495, PMC: PMC6545280, PMID: 30698716,

Authors

Cheng, Ching-Yu (8) (9) (10)
Sim, Xueling (8) (11)
Aschard, Hugues (17) (18)
Deng, Xuan (21)
Manning, Alisa K (18) (24)
Smith, Albert V (26) (27)
Chai, Jin Fang (8) (11)
Chen, Xu (33)
Gao, Chuan (34)
Goel, Anuj (36) (37)
He, Meian (41)
Kühnel, Brigitte (45) (46)
Pietzner, Maik (51) (52)
Riaz, Muhammad (53) (54)
Sofer, Tamar (18) (55)
Zhang, Weihua (30) (63)
Aung, Tin (8) (9) (64)
Boerwinkle, Eric (1) (66)
Duan, Qing (70)
Franco, Oscar H (12) (73)
Ghanbari, Mohsen (12) (75)
Heng, Chew-Kiat (8) (11)
Howard, Barbara V (78) (79)
Jonas, Jost Bruno (81) (82)
Koh, Woon-Puay (8) (11) (87)
Koistinen, Heikki A (88) (89) (90)
Lakka, Timo A (44) (56) (92)
Li, Yize (3)
Liu, Jianjun (8) (22)
Liu, Kiang (93)
Loh, Marie (30) (94)
Louie, Tin (19)
Meitinger, Thomas (96) (97)
Nalls, Mike A (28) (100)
Nauck, Matthias (51) (52)
Peters, Annette (45) (52)
Polasek, Ozren (102) (103) (104)
Raitakari, Olli T (106) (107)
Shi, Yuan (9)
Strauch, Konstantin (46) (112)
Tan, Nicholas (8) (9)
Teo, Yik Ying (8) (11) (22)
Wang, Zhe (1)
Yao, Jie (6)
Yu, Bing (1)
Zhao, Wei (20)
Chambers, John C (30) (63) (114) (115)
Esko, Tõnu (31) (116)
Farrall, Martin (36) (37)
Franks, Paul W (18) (59) (117) (118)
Froguel, Philippe (30) (32)
Gasparini, Paolo (35) (108)
Gieger, Christian (46) (119)
Kooner, Jaspal S (30) (63) (115)
Samani, Nilesh J (53) (54)
Watkins, Hugh (36) (37)
Zheng, Wei (61)
Elliott, Paul (30) (120) (121)
North, Kari E (7) (122)
Psaty, Bruce M (19) (123)
Ridker, Paul M (18) (55)
van Dam, Rob M (8) (11) (18)
Tai, E Shyong (8) (11) (87)
Wong, Tien Yin (8) (9) (64)
Chasman, Daniel I (18) (55)
Cupples, L Adrienne (21) (126)

Affiliations

Organisations

  1. (1) The University of Texas Health Science Center at Houston, grid.267308.8
  2. (2) National Human Genome Research Institute, grid.280128.1
  3. (3) Washington University in St. Louis, grid.4367.6
  4. (4) University of Regensburg, grid.7727.5
  5. (5) Queen Mary University of London, grid.4868.2
  6. (6) Harbor–UCLA Medical Center, grid.239844.0
  7. (7) Epidemiology, University of North Carolina Gilling School of Global Public Health, Chapel Hill, North Carolina
  8. (8) National University of Singapore, grid.4280.e
  9. (9) Singapore National Eye Center, grid.419272.b
  10. (10) Centre for Quantitative Medicine, Academic Medicine Research Institute, Ophthalmology & Visual Sciences Academic Clinical Program
  11. (11) National University Health System, grid.410759.e
  12. (12) Erasmus University Medical Center, grid.5645.2
  13. (13) University of Edinburgh, grid.4305.2
  14. (14) University of Mississippi Medical Center, grid.410721.1
  15. (15) Epidemiology and Biostatistics, University of Georgia at Athens College of Public Health, Athens, Georgia
  16. (16) Leiden University Medical Center, grid.10419.3d
  17. (17) Centre de Bioinformatique, Biostatistique et Biologie Intégrative
  18. (18) Harvard University, grid.38142.3c
  19. (19) University of Washington, grid.34477.33
  20. (20) University of Michigan, grid.214458.e
  21. (21) Boston University, grid.189504.1
  22. (22) Genome Institute of Singapore, grid.418377.e
  23. (23) Wake Forest Baptist Medical Center, grid.412860.9
  24. (24) Massachusetts General Hospital, grid.32224.35
  25. (25) Pennington Biomedical Research Center, grid.250514.7
  26. (26) Icelandic Heart Association, grid.420802.c
  27. (27) University of Iceland, grid.14013.37
  28. (28) National Institute on Aging, grid.419475.a
  29. (29) University of Ioannina, grid.9594.1
  30. (30) Imperial College London, grid.7445.2
  31. (31) University of Tartu, grid.10939.32
  32. (32) CNRS UMR 8199, European Genomic Institute for Diabetes
  33. (33) Karolinska Institute, grid.4714.6
  34. (34) Wake Forest University, grid.241167.7
  35. (35) University of Trieste, grid.5133.4
  36. (36) University of Oxford, grid.4991.5
  37. (37) Wellcome Centre for Human Genetics, grid.270683.8
  38. (38) University Medical Center Groningen, grid.4494.d
  39. (39) University of Bristol, grid.5337.2
  40. (40) Federal University of Pelotas, grid.411221.5
  41. (41) Huazhong University of Science and Technology, grid.33199.31
  42. (42) Laboratory of Genetics and Molecular Cardiology, Heart Institute
  43. (43) University of Kelaniya, grid.45202.31
  44. (44) Kuopion Liikuntalääketieteen Tutkimuslaitos, grid.419013.e
  45. (45) Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  46. (46) Helmholtz Zentrum München, grid.4567.0
  47. (47) Columbia University Medical Center, grid.239585.0
  48. (48) University of Cambridge, grid.5335.0
  49. (49) Tampere University, grid.502801.e
  50. (50) RIKEN, grid.7597.c
  51. (51) University of Greifswald, grid.5603.0
  52. (52) German Centre for Cardiovascular Research, grid.452396.f
  53. (53) Glenfield Hospital, grid.412925.9
  54. (54) University of Leicester, grid.9918.9
  55. (55) Brigham and Women's Hospital, grid.62560.37
  56. (56) University of Eastern Finland, grid.9668.1
  57. (57) National Center For Global Health and Medicine, grid.45203.30
  58. (58) Loyola University Chicago, grid.164971.c
  59. (59) Skåne University Hospital, grid.411843.b
  60. (60) Case Western Reserve University, grid.67105.35
  61. (61) Vanderbilt University, grid.152326.1
  62. (62) Johns Hopkins University, grid.21107.35
  63. (63) Ealing Hospital, grid.415918.0
  64. (64) Ophthalmology & Visual Sciences Academic Clinical Program
  65. (65) Houston Methodist, grid.63368.38
  66. (66) Baylor College of Medicine, grid.39382.33
  67. (67) Medical College of Wisconsin, grid.30760.32
  68. (68) University of Dundee, grid.8241.f
  69. (69) University of Glasgow, grid.8756.c
  70. (70) University of North Carolina at Chapel Hill, grid.10698.36
  71. (71) Brown University, grid.40263.33
  72. (72) University of the West Indies, grid.12916.3d
  73. (73) Institute of Social and Preventive Medicine, grid.482968.9
  74. (74) Hadassah Medical Center, grid.17788.31
  75. (75) Mashhad University of Medical Sciences, grid.411583.a
  76. (76) National Institutes of Health, grid.94365.3d
  77. (77) University of Tokyo, grid.26999.3d
  78. (78) Howard University, grid.257127.4
  79. (79) MedStar Health, grid.415232.3
  80. (80) University of Minnesota, grid.17635.36
  81. (81) Heidelberg University, grid.7700.0
  82. (82) Capital Medical University, grid.24696.3f
  83. (83) University of Pittsburgh, grid.21925.3d
  84. (84) Osaka University, grid.136593.b
  85. (85) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  86. (86) University of Copenhagen, grid.5254.6, KU
  87. (87) Duke NUS Graduate Medical School, grid.428397.3
  88. (88) Helsinki University Central Hospital, grid.15485.3d
  89. (89) Minerva Foundation, grid.452540.2
  90. (90) National Institute for Health and Welfare, grid.14758.3f
  91. (91) Fred Hutchinson Cancer Research Center, grid.270240.3
  92. (92) Kuopio University Hospital, grid.410705.7
  93. (93) Northwestern University, grid.16753.36
  94. (94) Agency for Science, Technology and Research, grid.185448.4
  95. (95) University of Virginia, grid.27755.32
  96. (96) Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  97. (97) Technical University of Munich, grid.6936.a
  98. (98) Department of Psychiatry, Amsterdam Neuroscience and Amsterdam Public Health Research Institute, Amsterdam University Medical Center, Amsterdam, The Netherlands
  99. (99) Beth Israel Deaconess Medical Center, grid.239395.7
  100. (100) Data Tecnica International, Glen Echo, Maryland
  101. (101) University of Maryland, Baltimore, grid.411024.2
  102. (102) Gen-info Ltd, Zagreb, Croatia
  103. (103) Psychiatric Hospital "Sveti Ivan", Zagreb, Croatia
  104. (104) University of Split, grid.38603.3e
  105. (105) University of California, Irvine, grid.266093.8
  106. (106) Turku University Hospital, grid.410552.7
  107. (107) University of Turku, grid.1374.1
  108. (108) IRCCS Materno Infantile Burlo Garofolo, grid.418712.9
  109. (109) University of Iowa, grid.214572.7
  110. (110) Kaiser Permanente, grid.280062.e
  111. (111) Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom
  112. (112) Ludwig Maximilian University of Munich, grid.5252.0
  113. (113) Jackson State University, grid.257990.0
  114. (114) Nanyang Technological University, grid.59025.3b
  115. (115) Imperial College Healthcare NHS Trust, grid.417895.6
  116. (116) Broad Institute, grid.66859.34
  117. (117) Oxford Centre for Diabetes, Endocrinology and Metabolism, grid.470392.b
  118. (118) Umeå University, grid.12650.30
  119. (119) German Center for Diabetes Research, grid.452622.5
  120. (120) Health Data Research UK, grid.507332.0
  121. (121) UK Dementia Research Institute
  122. (122) University of North Carolina System, grid.410711.2
  123. (123) Kaiser Permanente Washington Health Research Institute, grid.488833.c
  124. (124) Tulane University, grid.265219.b
  125. (125) University of Southern California, grid.42505.36
  126. (126) NHLBI Framingham Heart Study, Framingham, Massachusetts

Description

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

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Times Cited: 17

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