Article open access publication

Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent

PLoS Medicine, Public Library of Science (PLoS), ISSN 1549-1676

Volume 13, 8, 2016

DOI:10.1371/journal.pmed.1002105, Dimensions: pub.1027510142, PMC: PMC4995025, PMID: 27551723,

Authors

Guo, Yan (1)
Wang, Qin (3)
Milne, Roger L. (5) (6)
Bojesen, Stig E. (11) (12)
Andrulis, Irene L. (15) (16)
Benitez, Javier (18) (19)
Brauch, Hiltrud (9) (25) (26)
Fasching, Peter A. (33) (34)
Giles, Graham G (5) (6)
Guénel, Pascal (39) (40)
John, Esther M (43) (44)
Knight, Julia A. (16) (45)
Kosma, Veli-Matti (46) (47)
Kristensen, Vessela (22) (23) (48)
Mannermaa, Arto (46) (47)
Marme, Frederik (51) (52)
Phillips, Kelly-Anne (6) (61) (62)
Santella, Regina (64) (65)
Truong, Thérèse (39) (40)
Winqvist, Robert (63) (71)
Zhao, Hui (72) (73)
Hall, Per (24)
Zheng, Wei * (2)

* Corresponding author

Affiliations

Organisations

  1. (1) Vanderbilt University, grid.152326.1
  2. (2) Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
  3. (3) University of Cambridge, grid.5335.0
  4. (4) Institute of Cancer Research, grid.18886.3f
  5. (5) Cancer Council Victoria, grid.3263.4
  6. (6) University of Melbourne, grid.1008.9
  7. (7) Antoni van Leeuwenhoek Hospital, grid.430814.a
  8. (8) University of Ulm, grid.6582.9
  9. (9) German Cancer Research Center, grid.7497.d
  10. (10) University of Sheffield, grid.11835.3e
  11. (11) University of Copenhagen, grid.5254.6, KU
  12. (12) Herlev Hospital, grid.411900.d, Capital Region
  13. (13) University of Chicago, grid.170205.1
  14. (14) Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  15. (15) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  16. (16) University of Toronto, grid.17063.33
  17. (17) University of California, Irvine, grid.266093.8
  18. (18) Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain
  19. (19) Spanish National Cancer Research Centre, grid.7719.8
  20. (20) Hannover Medical School, grid.10423.34
  21. (21) European Institute of Oncology, grid.15667.33
  22. (22) Oslo University Hospital, grid.55325.34
  23. (23) University of Oslo, grid.5510.1
  24. (24) Karolinska Institute, grid.4714.6
  25. (25) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  26. (26) University of Tübingen, grid.10392.39
  27. (27) Ruhr University Bochum, grid.5570.7
  28. (28) University of Southern California, grid.42505.36
  29. (29) QIMR Berghofer Medical Research Institute, grid.1049.c
  30. (30) Mayo Clinic, grid.66875.3a
  31. (31) Leiden University Medical Center, grid.10419.3d
  32. (32) Laval University, grid.23856.3a
  33. (33) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  34. (34) University of California, Los Angeles, grid.19006.3e
  35. (35) National Cancer Institute, grid.48336.3a
  36. (36) University Medical Center Hamburg-Eppendorf, grid.13648.38
  37. (37) National Centre of Scientific Research Demokritos, grid.6083.d
  38. (38) University of North Carolina at Chapel Hill, grid.10698.36
  39. (39) French Institute of Health and Medical Research, grid.7429.8
  40. (40) University of Paris-Sud, grid.5842.b
  41. (41) Erasmus University Medical Center, grid.5645.2
  42. (42) Pomeranian Medical University, grid.107950.a
  43. (43) Cancer Prevention Institute of California, grid.280669.3
  44. (44) Stanford University, grid.168010.e
  45. (45) Mount Sinai Hospital, grid.416166.2
  46. (46) Kuopio University Hospital, grid.410705.7
  47. (47) University of Eastern Finland, grid.9668.1
  48. (48) Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway
  49. (49) University of Hawaii at Manoa, grid.410445.0
  50. (50) Fred Hutchinson Cancer Research Center, grid.270240.3
  51. (51) Heidelberg University, grid.7700.0
  52. (52) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
  53. (53) The Alfred Hospital, grid.1623.6
  54. (54) VU University Medical Center, grid.16872.3a
  55. (55) Technical University of Munich, grid.6936.a
  56. (56) City Of Hope National Medical Center, grid.410425.6
  57. (57) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  58. (58) Universitair Ziekenhuis Leuven, grid.410569.f
  59. (59) Hospital Monte Naranco, grid.414858.4
  60. (60) IFOM, Fondazione Istituto FIRC (Italian Foundation of Cancer Research) di Oncologia Molecolare, Milan, Italy
  61. (61) Department of Medicine, St Vincent's Hospital, The University of Melbourne, Fitzroy, Australia
  62. (62) Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia
  63. (63) University of Oulu, grid.10858.34
  64. (64) Columbia University, grid.21729.3f
  65. (65) Columbia University Medical Center, grid.239585.0
  66. (66) King's College London, grid.13097.3c
  67. (67) University Hospital Cologne, grid.411097.a
  68. (68) The Ohio State University, grid.261331.4
  69. (69) University of Oxford, grid.4991.5
  70. (70) University Medical Center Utrecht, grid.7692.a
  71. (71) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland
  72. (72) KU Leuven, grid.5596.f
  73. (73) Vesalius Research Center, Leuven, Belgium
  74. (74) Harvard University, grid.38142.3c

Description

BACKGROUND: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. METHODS: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. RESULTS: In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31-0.62, p  =  9.91 × 10-8) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46-0.71, p  =  1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60-0.84, p   =   1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. CONCLUSIONS: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

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Times Cited: 60

Field Citation Ratio (FCR): 17.57

Relative Citation ratio (RCR): 3.63

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