. 2016 Aug 23;13(8):e1002105.

doi: 10.1371/journal.pmed.1002105. eCollection 2016 Aug.

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

Yan Guo¹, Shaneda Warren Andersen², Xiao-Ou Shu², Kyriaki Michailidou³, Manjeet K Bolla³, Qin Wang³, Montserrat Garcia-Closas^{4

5}, Roger L Milne^{6

7}, Marjanka K Schmidt⁸, Jenny Chang-Claude^{9

10}, Allison Dunning¹¹, Stig E Bojesen^{12

13

14}, Habibul Ahsan¹⁵, Kristiina Aittomäki¹⁶, Irene L Andrulis^{17

18}, Hoda Anton-Culver¹⁹, Volker Arndt²⁰, Matthias W Beckmann¹⁵, Alicia Beeghly-Fadiel², Javier Benitez^{21

22}, Natalia V Bogdanova²³, Bernardo Bonanni²⁴, Anne-Lise Børresen-Dale^{25

26}, Judith Brand²⁷, Hiltrud Brauch^{28

29

30}, Hermann Brenner^{20

28

31}, Thomas Brüning³², Barbara Burwinkel^{33

34}, Graham Casey³⁵, Georgia Chenevix-Trench³⁶, Fergus J Couch³⁷, Angela Cox³⁸, Simon S Cross¹¹, Kamila Czene²⁷, Peter Devilee³⁹, Thilo Dörk⁴⁰, Martine Dumont⁴¹, Peter A Fasching^{42

43}, Jonine Figueroa⁴⁴, Dieter Flesch-Janys^{45

46}, Olivia Fletcher⁵, Henrik Flyger⁴⁷, Florentia Fostira⁴⁸, Marilie Gammon⁴⁹, Graham G Giles^{6

7}, Pascal Guénel^{50

51}, Christopher A Haiman³⁵, Ute Hamann⁵², Maartje J Hooning⁵³, John L Hopper⁷, Anna Jakubowska⁵⁴, Farzana Jasmine¹⁵, Mark Jenkins⁷, Esther M John^{55

56}, Nichola Johnson⁵, Michael E Jones⁴, Maria Kabisch⁵², Muhammad Kibriya¹⁵, Julia A Knight^{57

58}, Linetta B Koppert⁵³, Veli-Matti Kosma^{59

60

61}, Vessela Kristensen^{25

26

62}, Loic Le Marchand⁶³, Eunjung Lee³⁵, Jingmei Li²⁷, Annika Lindblom⁶⁴, Robert Luben⁶⁵, Jan Lubinski⁵⁴, Kathi E Malone⁶⁶, Arto Mannermaa^{59

60

61}, Sara Margolin⁶⁷, Frederik Marme^{68

69}, Catriona McLean⁷⁰, Hanne Meijers-Heijboer⁷¹, Alfons Meindl⁷², Susan L Neuhausen⁷³, Heli Nevanlinna⁷⁴, Patrick Neven⁷⁵, Janet E Olson⁷⁶, Jose I A Perez⁷⁷, Barbara Perkins⁷⁸, Paolo Peterlongo⁷⁹, Kelly-Anne Phillips^{80

81

82}, Katri Pylkäs⁸³, Anja Rudolph⁹, Regina Santella^{84

85}, Elinor J Sawyer⁸⁶, Rita K Schmutzler^{87

88

89

90}, Caroline Seynaeve⁵³, Mitul Shah⁷⁸, Martha J Shrubsole², Melissa C Southey⁹¹, Anthony J Swerdlow^{4

92}, Amanda E Toland⁹³, Ian Tomlinson⁹⁴, Diana Torres⁵², Thérèse Truong^{50

51}, Giske Ursin⁹⁵, Rob B Van Der Luijt⁹⁶, Senno Verhoef⁸, Alice S Whittemore⁵⁶, Robert Winqvist^{83

97}, Hui Zhao^{98

99}, Shilin Zhao¹, Per Hall²⁷, Jacques Simard⁴¹, Peter Kraft^{100

101}, Paul Pharoah^{3

78}, David Hunter^{100

101}, Douglas F Easton^{3

78}, Wei Zheng²

Affiliations

¹ Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
² Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
³ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
⁴ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
⁵ Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
⁶ Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
⁷ Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Australia.
⁸ Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
⁹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
¹¹ Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom.
¹² Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹³ Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
¹⁴ Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
¹⁵ Department of Health Studies, The University of Chicago, Chicago, Illinois, United States of America.
¹⁶ Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
¹⁷ Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
¹⁸ Department of Molecular Genetics, University of Toronto, Toronto, Canada.
¹⁹ Department of Epidemiology, University of California Irvine, Irvine, California, United States of America.
²⁰ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²¹ Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
²² Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain.
²³ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
²⁴ Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
²⁵ Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, Oslo University Hospital, Oslo, Norway.
²⁶ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
²⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁸ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁹ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
³⁰ University of Tübingen, Tübingen, Germany.
³¹ Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³² Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany.
³³ Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁴ Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁵ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
³⁶ Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
³⁷ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
³⁸ Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, United Kingdom.
³⁹ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁴⁰ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
⁴¹ Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
⁴² Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
⁴³ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California, United States of America.
⁴⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America.
⁴⁵ Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁶ Department of Cancer Epidemiology, Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁷ Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁴⁸ Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Athens, Greece.
⁴⁹ Departments of Epidemiology, University of North Carolina Chapel-Hill, Chapel Hill, North Carolina, United States of America.
⁵⁰ Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France.
⁵¹ University Paris-Sud, Villejuif, France.
⁵² Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵³ Department of Surgical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁵⁴ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
⁵⁵ Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, United States of America.
⁵⁶ Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, United States of America.
⁵⁷ Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
⁵⁸ Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
⁵⁹ Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
⁶⁰ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
⁶¹ Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
⁶² Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
⁶³ University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America.
⁶⁴ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁶⁵ Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
⁶⁶ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
⁶⁷ Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
⁶⁸ National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
⁶⁹ Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
⁷⁰ Anatomical Pathology, The Alfred Hospital, Melbourne, Australia.
⁷¹ Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
⁷² Division of Gynaecology and Obstetrics, Technische Universit��t München, Munich, Germany.
⁷³ Beckman Research Institute of City of Hope, Duarte, California, United States of America.
⁷⁴ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁷⁵ Department of Oncology, University Hospital Gasthuisberg, Leuven, Belgium.
⁷⁶ Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.
⁷⁷ Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain.
⁷⁸ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
⁷⁹ IFOM, Fondazione Istituto FIRC (Italian Foundation of Cancer Research) di Oncologia Molecolare, Milan, Italy.
⁸⁰ Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia.
⁸¹ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
⁸² Department of Medicine, St Vincent's Hospital, The University of Melbourne, Fitzroy, Australia.
⁸³ Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland.
⁸⁴ Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America.
⁸⁵ Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, New York, United States of America.
⁸⁶ Research Oncology, Guy's Hospital, King's College London, London, United Kingdom.
⁸⁷ Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany.
⁸⁸ Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany.
⁸⁹ Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany.
⁹⁰ Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
⁹¹ Department of Pathology, The University of Melbourne, Melbourne, Australia.
⁹² Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom.
⁹³ Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
⁹⁴ Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
⁹⁵ Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
⁹⁶ Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
⁹⁷ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
⁹⁸ Vesalius Research Center, Leuven, Belgium.
⁹⁹ Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
¹⁰⁰ Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, United States of America.
¹⁰¹ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.

PMID: 27551723
PMCID: PMC4995025
DOI: 10.1371/journal.pmed.1002105

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

Yan Guo et al. PLoS Med. 2016.

. 2016 Aug 23;13(8):e1002105.

doi: 10.1371/journal.pmed.1002105. eCollection 2016 Aug.

Authors

Affiliations

¹ Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
² Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
³ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
⁴ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
⁵ Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
⁶ Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
⁷ Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Australia.
⁸ Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
⁹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
¹¹ Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom.
¹² Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹³ Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
¹⁴ Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
¹⁵ Department of Health Studies, The University of Chicago, Chicago, Illinois, United States of America.
¹⁶ Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
¹⁷ Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
¹⁸ Department of Molecular Genetics, University of Toronto, Toronto, Canada.
¹⁹ Department of Epidemiology, University of California Irvine, Irvine, California, United States of America.
²⁰ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²¹ Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
²² Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain.
²³ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
²⁴ Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
²⁵ Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, Oslo University Hospital, Oslo, Norway.
²⁶ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
²⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁸ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁹ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
³⁰ University of Tübingen, Tübingen, Germany.
³¹ Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³² Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany.
³³ Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁴ Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁵ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
³⁶ Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
³⁷ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
³⁸ Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, United Kingdom.
³⁹ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁴⁰ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
⁴¹ Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
⁴² Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
⁴³ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California, United States of America.
⁴⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America.
⁴⁵ Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁶ Department of Cancer Epidemiology, Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁷ Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁴⁸ Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Athens, Greece.
⁴⁹ Departments of Epidemiology, University of North Carolina Chapel-Hill, Chapel Hill, North Carolina, United States of America.
⁵⁰ Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France.
⁵¹ University Paris-Sud, Villejuif, France.
⁵² Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵³ Department of Surgical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁵⁴ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
⁵⁵ Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, United States of America.
⁵⁶ Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, United States of America.
⁵⁷ Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
⁵⁸ Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
⁵⁹ Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
⁶⁰ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
⁶¹ Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
⁶² Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
⁶³ University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America.
⁶⁴ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁶⁵ Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
⁶⁶ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
⁶⁷ Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
⁶⁸ National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
⁶⁹ Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
⁷⁰ Anatomical Pathology, The Alfred Hospital, Melbourne, Australia.
⁷¹ Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
⁷² Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
⁷³ Beckman Research Institute of City of Hope, Duarte, California, United States of America.
⁷⁴ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁷⁵ Department of Oncology, University Hospital Gasthuisberg, Leuven, Belgium.
⁷⁶ Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.
⁷⁷ Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain.
⁷⁸ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
⁷⁹ IFOM, Fondazione Istituto FIRC (Italian Foundation of Cancer Research) di Oncologia Molecolare, Milan, Italy.
⁸⁰ Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia.
⁸¹ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
⁸² Department of Medicine, St Vincent's Hospital, The University of Melbourne, Fitzroy, Australia.
⁸³ Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland.
⁸⁴ Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America.
⁸⁵ Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, New York, United States of America.
⁸⁶ Research Oncology, Guy's Hospital, King's College London, London, United Kingdom.
⁸⁷ Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany.
⁸⁸ Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany.
⁸⁹ Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany.
⁹⁰ Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
⁹¹ Department of Pathology, The University of Melbourne, Melbourne, Australia.
⁹² Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom.
⁹³ Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
⁹⁴ Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
⁹⁵ Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
⁹⁶ Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
⁹⁷ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
⁹⁸ Vesalius Research Center, Leuven, Belgium.
⁹⁹ Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
¹⁰⁰ Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, United States of America.
¹⁰¹ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.

PMID: 27551723
PMCID: PMC4995025
DOI: 10.1371/journal.pmed.1002105

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

**Fig 1. Meta-analysis of the association between genetically predicted BMI and breast cancer risk in the BCAC.**
The summary OR was calculated by combining individual analysis results from each study in BCAC (p for heterogeneity = 0.06).

**Fig 2. Sensitivity analyses using pooled data for associations between genetically predicted BMI and breast cancer risk in the BCAC.**
(A) Adjusted for age, study sites, and the first eight principal components. (b) Adjusted for age, study sites, the first eight principal components, and additional breast cancer risk factors: age at menarche, parity, use of contraceptive, use of hormone replacement therapy, breast feeding, and smoking status. Weighted: the BMI-GS was constructed using the additive model weighted by external beta reported from previous literatures. Unweighted: the BMI-GS was constructed using the additive model without any weight.

See this image and copyright information in PMC

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

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

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