Article open access publication

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Nature Communications, Springer Nature, ISSN 2041-1723

Volume 7, 1, 2016

DOI:10.1038/ncomms10494, Dimensions: pub.1050053122, PMC: PMC4740377, PMID: 26833098,

Authors

Kilpeläinen, Tuomas O. * (1) (2) (3)
Sun, Qi (5) (6)
Kriebel, Jennifer (7) (8) (9)
Hedman, Åsa K (11) (12)
Hayes, James E (3) (13)
Pers, Tune H. (2) (5) (14) (15) (16)
Kutalik, Zoltán (17) (18)
Mangino, Massimo (20) (21)
Kristiansson, Kati (22) (23)
Henneman, Peter (19) (26)
Lahti, Jari (22) (27)
Renström, Frida (31) (32)
Gaunt, Tom (38)
Ahluwalia, Tarunveer S. (2) (39) (40)
Barroso, Inês (42) (43) (44)
Bellis, Claire (45) (46) (47)
Demirkan, Ayse (19) (33)
Ford, Ian (51)
Hankinson, Susan E (5) (6) (53)
Illig, Thomas (7) (55)
Ingelsson, Erik (11) (56)
Jørgensen, Torben (2) (58) (59)
Koenig, Wolfgang (61) (62) (63)
Laatikainen, Tiina (23) (64) (65)
Morris, Andrew P. (12) (67)
Peters, Annette (8) (9) (63)
Brent Richards, J (21) (50)
Ridker, Paul M. (5) (6)
Wichmann, Heinz-Erich (62) (73) (74)
Yao, Jie (34)
Zeller, Tanja (63) (75)
Sørensen, Thorkild I A (2) (38) (76)
Rao, D C (10)
Kajantie, Eero (23) (77) (78)
Palotie, Aarno (22) (44) (80)
Eriksson, Johan G. (22) (23) (27)
Perola, Markus (22) (23) (81)
Viikari, Jorma S A (82) (83)
Kähönen, Mika (24) (84)
Raitakari, Olli T. (82) (83)
März, Winfried (36) (87) (88)
Lind, Lars (11)
Pramstaller, Peter P. (29) (91) (92)
Bergmann, Sven (18) (94)
Hansen, Torben (2) (95)
Grallert, Harald (7) (8) (9)
Jukema, J.W. (19) (96) (97)
Franks, Paul W. (5) (31) (32)
Lindgren, Cecilia M. (12) (16) (98)
Loos, Ruth J F * (1) (3)

* Corresponding author

Affiliations

Organisations

  1. (1) Institute of Metabolic Science, grid.470900.a
  2. (2) University of Copenhagen, grid.5254.6, KU
  3. (3) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  4. (4) Columbia University, grid.21729.3f
  5. (5) Harvard University, grid.38142.3c
  6. (6) Brigham and Women's Hospital, grid.62560.37
  7. (7) Helmholtz Zentrum München, grid.4567.0
  8. (8) Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764, Neuherberg, Germany
  9. (9) German Center for Diabetes Research, grid.452622.5
  10. (10) Washington University in St. Louis, grid.4367.6
  11. (11) Uppsala University, grid.8993.b
  12. (12) Wellcome Centre for Human Genetics, grid.270683.8
  13. (13) Cornell University, grid.5386.8
  14. (14) Boston Children's Hospital, grid.2515.3
  15. (15) State Serum Institute, grid.6203.7
  16. (16) Broad Institute, grid.66859.34
  17. (17) Institute of Social and Preventive Medicine, grid.482968.9
  18. (18) Swiss Institute of Bioinformatics, grid.419765.8
  19. (19) Leiden University Medical Center, grid.10419.3d
  20. (20) National Institute for Health Research, grid.451056.3
  21. (21) Department of Twin Research and Genetic Epidemiology King’s College London, SE1 7EH, London, UK
  22. (22) University of Helsinki, grid.7737.4
  23. (23) National Institute for Health and Welfare, grid.14758.3f
  24. (24) Tampere University, grid.502801.e
  25. (25) University of Gothenburg, grid.8761.8
  26. (26) Academic Medical Center, grid.5650.6
  27. (27) Folkhälsans Forskningscentrum, grid.428673.c
  28. (28) National Institute on Aging, grid.419475.a
  29. (29) European Academy of Bozen, grid.418908.c
  30. (30) University of Exeter, grid.8391.3
  31. (31) Lund University, grid.4514.4
  32. (32) Umeå University, grid.12650.30
  33. (33) Erasmus University Medical Center, grid.5645.2
  34. (34) University of California, Los Angeles, grid.19006.3e
  35. (35) Center for Human Genetics, grid.492411.b
  36. (36) Vth Department of Medicine Heidelberg University, Medical Faculty Mannheim, 68167, Mannheim, Germany
  37. (37) Laval University, grid.23856.3a
  38. (38) University of Bristol, grid.5337.2
  39. (39) COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Ledreborg Allé, DK-2820, Copenhagen, Denmark
  40. (40) Steno Diabetes Center, grid.419658.7, Capital Region
  41. (41) London School of Hygiene & Tropical Medicine, grid.8991.9
  42. (42) NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke’s Hospital, CB2 0QQ, Cambridge, UK
  43. (43) University of Cambridge, grid.5335.0
  44. (44) Wellcome Sanger Institute, grid.10306.34
  45. (45) Genome Institute of Singapore, grid.418377.e
  46. (46) Queensland University of Technology, grid.1024.7
  47. (47) Texas Biomedical Research Institute, grid.250889.e
  48. (48) University College Cork, grid.7872.a
  49. (49) University of Washington, grid.34477.33
  50. (50) McGill University, grid.14709.3b
  51. (51) University of Glasgow, grid.8756.c
  52. (52) National Heart Lung and Blood Institute, grid.279885.9
  53. (53) University of Massachusetts Amherst, grid.266683.f
  54. (54) German Diabetes Center - Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, grid.429051.b
  55. (55) Hannover Medical School, grid.10423.34
  56. (56) Stanford University, grid.168010.e
  57. (57) University of Vermont, grid.59062.38
  58. (58) Aalborg University, grid.5117.2, AAU
  59. (59) Rigshospitalet, grid.475435.4, Capital Region
  60. (60) Department of Clinical Sciences and Orthopaedic Surgery, Clinical and Molecular Osteoporosis Research Unit, Lund University, Skåne University Hospital, 21428, Malmö, Sweden
  61. (61) University of Ulm, grid.6582.9
  62. (62) Technical University of Munich, grid.6936.a
  63. (63) German Centre for Cardiovascular Research, grid.452396.f
  64. (64) Hospital District of North Karelia, FI-80210, Joensuu, Finland
  65. (65) University of Eastern Finland, grid.9668.1
  66. (66) University Hospital of Lausanne, grid.8515.9
  67. (67) University of Liverpool, grid.10025.36
  68. (68) Boston University School of Medicine, grid.475010.7
  69. (69) Pennington Biomedical Research Center, grid.250514.7
  70. (70) Northwestern University, grid.16753.36
  71. (71) Faculty of Medicine, BHF Glasgow Cardiovascular Research Centre, G12 8QQ, Glasgow, UK
  72. (72) Newcastle University, grid.1006.7
  73. (73) Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764, Neuherberg, Germany
  74. (74) Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität and Klinikum Grosshadern, 80336, Munich, Germany
  75. (75) University Medical Center Hamburg-Eppendorf, grid.13648.38
  76. (76) Frederiksberg Hospital, grid.415046.2, Capital Region
  77. (77) Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Central Hospital and University of Oulu, 90220, Oulu, Finland
  78. (78) Helsinki Children's Hospital, grid.424592.c
  79. (79) MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, SO16 6YD, Southampton, UK
  80. (80) Massachusetts General Hospital, grid.32224.35
  81. (81) University of Tartu, grid.10939.32
  82. (82) Turku University Hospital, grid.410552.7
  83. (83) University of Turku, grid.1374.1
  84. (84) Tampere University Hospital, grid.412330.7
  85. (85) University College London, grid.83440.3b
  86. (86) Azienda Sanitaria di Firenze, grid.423864.f
  87. (87) Medical University of Graz, grid.11598.34
  88. (88) Synlab Academy, Synlab Services LLC, 68161, Mannheim, Germany
  89. (89) Center of Medical Systems Biology, 2300 RC, Leiden, The Netherlands
  90. (90) University of California, San Diego, grid.266100.3
  91. (91) Ospedale di Bolzano, grid.415844.8
  92. (92) University of Lübeck, grid.4562.5
  93. (93) GlaxoSmithKline (United States), grid.418019.5
  94. (94) University of Lausanne, grid.9851.5
  95. (95) University of Southern Denmark, grid.10825.3e, SDU
  96. (96) Durrer Center for Cardiogenetic Research, 1105 AZ, Amsterdam, The Netherlands
  97. (97) Netherlands Heart Institute, grid.411737.7
  98. (98) University of Oxford, grid.4991.5

Description

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

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University of Copenhagen

Aalborg University

University of Southern Denmark

Danish Open Access Indicator

2016: Realized

Research area: Medicine

Danish Bibliometrics Indicator

2016: Level 2

Research area: Medicine

Dimensions Citation Indicators

Times Cited: 74

Field Citation Ratio (FCR): 12.38

Relative Citation ratio (RCR): 3.77

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