Article open access publication

New genetic loci link adipose and insulin biology to body fat distribution

Nature, Springer Nature, ISSN 1476-4687

Volume 518, 7538, 2015

DOI:10.1038/nature14132, Dimensions: pub.1019263071, PMC: PMC4338562, PMID: 25673412,

Authors

Shungin, Dmitry (1) (2)
Mägi, Reedik (6) (8)
Pers, Tune H. (10) (11) (12) (13)
Song, Ci (9) (17)
Esko, Tonu (8) (11) (12) (13)
Fall, Tove (9) (17)
Kutalik, Zoltán (19) (20) (21)
Scherag, André (23) (24)
Vedantam, Sailaja (12) (13)
Chen, Jin (7)
Demirkan, Ayse (28) (30)
Ehret, Georg B (32) (33)
Goel, Anuj (6) (35)
Johnson, Toby (20) (21) (36)
Kleber, Marcus E. (37) (38)
Palmer, Cameron D (12) (13)
Prokopenko, Inga (6) (35) (43)
Yengo, Loic (48) (49) (50)
Zhang, Weihua (43) (51)
Ärnlöv, Johan (17) (53)
Bellis, Claire (56) (57)
Eklund, Niina (39) (65)
Estrada, Karol (13) (28) (67)
Eury, Elodie (48) (49) (50)
Grallert, Harald (52) (70)
Grewal, Jagvir (43) (51)
Herzig, Karl-Heinz (74) (75)
Helmer, Quinta (30) (76)
Hillege, Hans L (41) (77)
Isaacs, Aaron (28) (79)
James, Alan L (29) (80)
Lind, Lars (17)
Lobbens, Stéphane (48) (49) (50)
Moayyeri, Alireza (40) (87)
Monda, Keri L (4) (88)
Müller-Nurasyid, Martina (52) (92) (93) (94)
Rayner, Nigel W. (6) (22) (35)
Stirrups, Kathleen (22) (101)
Thorand, Barbara (52) (70)
Wong, Andrew (106)
Choi, Mu Rim (108)
Hedman, Åsa K (6) (17)
Huang, Jinyan (11) (110)
Karpe, Fredrik (35) (111)
Ma, Baoshan (11) (113)
Murabito, Joanne M (15) (16)
Nicholson, George (35) (117)
Nyholt, Dale R (56) (116)
Perry, John R B (6) (25) (40)
Salem, Rany M (11) (12) (13)
Sandholm, Niina (65) (118) (119)
Stolk, Lisette (28) (30)
Amouyel, Philippe (122) (123)
Beilby, John (29) (54)
Crawford, Dana C (129) (130)
Danesh, John (126)
De Geus, Eco J C N (76) (131)
Dörr, Marcus (46) (93)
Eriksson, Johan G. (39) (65) (119)
Farrall, Martin (6) (35)
Ferrannini, Ele (132) (133)
Franco, Oscar H. (28) (42)
Gudnason, Vilmundur (99) (100)
Hoffmann, Wolfgang (46) (93)
Hofman, Albert (28) (42)
Hyppönen, Elina (87) (137) (138)
Illig, Thomas (52) (139)
Jarvelin, Marjo-Riitta (39) (43) (74) (75)
Kaprio, Jaakko (39) (65)
Kee, Frank (114)
Kooner, Jaspal S. (43) (51) (140)
Kumari, Meena (87) (142)
Lakka, Timo A. (44) (72)
Lyssenko, Valeriya (2) (145)
Ong, Ken K L (18) (106)
Palmer, Lyle J. (147) (148)
Peters, Annette (52) (93)
Pramstaller, Peter P. (136) (149)
Raitakari, Olli T. (150) (151)
Rao, D C (34)
Ridker, Paul M (5) (11)
Rudan, Igor (128) (154)
Samani, Nilesh J. (155) (156)
Schwarz, Peter E H (71) (158)
Shuldiner, Alan R (159) (160)
Staessen, Jan A. (161) (162)
Völker, Uwe (46) (93)
Bochud, Murielle (19) (165)
Boehm, Bernhard O. (82) (166)
Cauchi, Stéphane (48) (49) (50)
Chambers, John C. (43) (51) (140)
Froguel, Philippe (43) (48) (49) (50)
Grabe, Hans Jörgen (46) (167)
Hui, Jennie (29) (54)
Kuh, Diana (106)
Liu, Yongmei (168)
März, Winfried (38) (97) (169)
Oostra, Ben A (28) (79)
Perola, Markus (8) (39) (65)
Rauramaa, Rainer (44) (72)
Saaristo, Timo E (171) (172)
Saleheen, Danish (126) (173) (174)
Tuomilehto, Jaakko (39) (175) (176) (177)
Uusitupa, Matti (44) (178)
van der Harst, Pim (26) (41) (179)
Walker, Mark (181)
Watkins, Hugh (6) (35)
Wichmann, H-Erich (52) (94) (182)
Deloukas, Panos (22) (101) (177)
Groop, Leif C. (2) (65)
Hunter, David J. (5) (11)
Qi, Lu (5)
Stefansson, Kari (100) (103)
van Duijn, Cornelia M. (28) (42) (79)
Yang, Jian (184)
Hirschhorn, Joel N (11) (12) (13)
McCarthy, Mark I. (6) (35) (111)
Barroso, Inês (18) (22) (185)
Franks, Paul W. (1) (2)
Ingelsson, Erik (6) (17)
Heid, Iris M (3) (52)
Loos, Ruth J F (18) (120)
Morris, Andrew P. (6) (8) (186)

* Corresponding author

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  2. (2) Lund University, grid.4514.4
  3. (3) University of Regensburg, grid.7727.5
  4. (4) University of North Carolina at Chapel Hill, grid.10698.36
  5. (5) Brigham and Women's Hospital, grid.62560.37
  6. (6) Wellcome Centre for Human Genetics, grid.270683.8
  7. (7) University of Michigan, grid.214458.e
  8. (8) University of Tartu, grid.10939.32
  9. (9) Karolinska Institute, grid.4714.6
  10. (10) Technical University of Denmark, grid.5170.3, DTU
  11. (11) Harvard University, grid.38142.3c
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  16. (16) National Heart Lung and Blood Institute, grid.279885.9
  17. (17) Uppsala University, grid.8993.b
  18. (18) Institute of Metabolic Science, grid.470900.a
  19. (19) Institute of Social and Preventive Medicine, grid.482968.9
  20. (20) Swiss Institute of Bioinformatics, grid.419765.8
  21. (21) University of Lausanne, grid.9851.5
  22. (22) Wellcome Sanger Institute, grid.10306.34
  23. (23) Jena University Hospital, grid.275559.9
  24. (24) Essen University Hospital, grid.410718.b
  25. (25) University of Exeter, grid.8391.3
  26. (26) Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
  27. (27) HudsonAlpha Institute for Biotechnology, grid.417691.c
  28. (28) Erasmus University Medical Center, grid.5645.2
  29. (29) University of Western Australia, grid.1012.2
  30. (30) Leiden University Medical Center, grid.10419.3d
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  36. (36) University Institute for Social and Preventative Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Lausanne 1005, Switzerland.
  37. (37) University Hospital Ulm, grid.410712.1
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  39. (39) National Institute for Health and Welfare, grid.14758.3f
  40. (40) King's College London, grid.13097.3c
  41. (41) Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands.
  42. (42) Netherlands Consortium for Healthy Ageing, grid.452197.c
  43. (43) Imperial College London, grid.7445.2
  44. (44) University of Eastern Finland, grid.9668.1
  45. (45) National Institute on Aging, grid.419475.a
  46. (46) University of Greifswald, grid.5603.0
  47. (47) University Medical Center Groningen, grid.4494.d
  48. (48) European Genomic Institute for Diabetes, grid.452394.d
  49. (49) Integrated Genomics and Metabolic Diseases Modeling, grid.463858.4
  50. (50) University of Lille, grid.503422.2
  51. (51) Ealing Hospital NHS Trust, grid.412922.e
  52. (52) Helmholtz Zentrum München, grid.4567.0
  53. (53) Dalarna University, grid.411953.b
  54. (54) Pathwest Laboratory Medicine, grid.2824.c
  55. (55) Azienda Sanitaria di Firenze, grid.423864.f
  56. (56) Queensland University of Technology, grid.1024.7
  57. (57) Texas Biomedical Research Institute, grid.250889.e
  58. (58) Leipzig University, grid.9647.c
  59. (59) University of Rennes 1, grid.410368.8
  60. (60) LifeLines Cohort Study, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
  61. (61) University of San Carlos, grid.267101.3
  62. (62) Norwegian University of Science and Technology, grid.5947.f
  63. (63) University of Southern California, grid.42505.36
  64. (64) Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
  65. (65) University of Helsinki, grid.7737.4
  66. (66) National Human Genome Research Institute, grid.280128.1
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  68. (68) National Institute of Arthritis and Musculoskeletal and Skin Diseases, grid.420086.8
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  70. (70) German Center for Diabetes Research, grid.452622.5
  71. (71) Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 Dresden, Germany.
  72. (72) Kuopion Liikuntalääketieteen Tutkimuslaitos, grid.419013.e
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  76. (76) VU Amsterdam, grid.12380.38
  77. (77) Department of Epidemiology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
  78. (78) University of Utah, grid.223827.e
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  80. (80) Sir Charles Gairdner Hospital, grid.3521.5
  81. (81) Harokopio University, grid.15823.3d
  82. (82) University of Ulm, grid.6582.9
  83. (83) Innsbruck Medical University, grid.5361.1
  84. (84) Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
  85. (85) University of Gothenburg, grid.8761.8
  86. (86) University of Bristol, grid.5337.2
  87. (87) University College London, grid.83440.3b
  88. (88) Amgen (United States), grid.417886.4
  89. (89) University of Bonn, grid.10388.32
  90. (90) Institute of Genetic and Biomedical Research, grid.428485.7
  91. (91) Center for Evidence-based Healthcare, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 Dresden, Germany.
  92. (92) Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, D-81377 Munich, Germany.
  93. (93) German Centre for Cardiovascular Research, grid.452396.f
  94. (94) Ludwig Maximilian University of Munich, grid.5252.0
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  100. (100) University of Iceland, grid.14013.37
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  102. (102) Loyola University Chicago, grid.164971.c
  103. (103) deCODE Genetics (Iceland), grid.421812.c
  104. (104) Department of Clinical Chemistry, Ulm University Medical Centre, D-89081 Ulm, Germany.
  105. (105) The Arctic University of Norway, grid.10919.30
  106. (106) MRC Unit for Lifelong Health and Ageing, grid.268922.5
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  110. (110) Shanghai Institute of Hematology, grid.410656.0
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  113. (113) Dalian Maritime University, grid.440686.8
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  116. (116) QIMR Berghofer Medical Research Institute, grid.1049.c
  117. (117) Medical Research Council Harwell, grid.420006.0
  118. (118) Aalto University, grid.5373.2
  119. (119) Helsinki University Central Hospital, grid.15485.3d
  120. (120) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  121. (121) Monterrey Institute of Technology and Higher Education, grid.419886.a
  122. (122) INSERM, U744
  123. (123) Institut Pasteur de Lille; INSERM, U744; Université de Lille 2; F-59000 Lille, France.
  124. (124) University of Strasbourg, grid.11843.3f
  125. (125) Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands.
  126. (126) University of Cambridge, grid.5335.0
  127. (127) University Hospital of Lausanne, grid.8515.9
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  130. (130) Vanderbilt University Medical Center, grid.412807.8
  131. (131) EMGO Institute for Health and Care Research, grid.466632.3
  132. (132) National Research Council Institute of Clinical Physiology, University of Pisa, Pisa 56124, Italy.
  133. (133) University of Pisa, grid.5395.a
  134. (134) Hôpital Rangueil, grid.414295.f
  135. (135) University of the West Indies, grid.12916.3d
  136. (136) European Academy of Bozen, grid.418908.c
  137. (137) South Australian Health and Medical Research Institute, grid.430453.5
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  139. (139) Hannover Medical School, grid.10423.34
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  155. (155) Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK.
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  163. (163) Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano & Centro Cardiologico Monzino, Instituto di Ricovero e Cura a Carattere Scientifico, Milan 20133, Italy.
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  166. (166) Nanyang Technological University, grid.59025.3b
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  185. (185) NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 OQQ, UK.
  186. (186) University of Liverpool, grid.10025.36

Description

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

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Technical University of Denmark

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2015: Unused

Research area: Science & Technology

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2015: Level 2

Research area: Science & Technology

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Times Cited: 724

Field Citation Ratio (FCR): 97.5

Relative Citation ratio (RCR): 33.19

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Green, Accepted