title: Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer.
abstract: Adiposity traits have been associated with risk of many cancers in observational studies, but whether these associations are causal is unclear. Mendelian randomization (MR) uses genetic predictors of risk factors as instrumental variables to eliminate reverse causation and reduce confounding bias. We performed MR analyses to assess the possible causal relationship of birthweight, childhood and adult body mass index (BMI), and waist-hip ratio (WHR) on the risks of breast, ovarian, prostate, colorectal and lung cancers.
  
  
  
  We tested the association between genetic risk scores and each trait using summary statistics from published genome-wide association studies (GWAS) and from 51 537 cancer cases and 61 600 controls in the Genetic Associations and Mechanisms in Oncology (GAME-ON) Consortium.
  
  
  
  We found an inverse association between the genetic score for childhood BMI and risk of breast cancer [odds ratio (OR) = 0.71 per standard deviation (s.d.) increase in childhood BMI; 95% confidence interval (CI): 0.60, 0.80; P = 6.5 × 10(-5)). We also found the genetic score for adult BMI to be inversely associated with breast cancer risk (OR = 0.66 per s.d. increase in BMI; 95% CI: 0.57, 0.77; P = 2.5 × 10(-7)), and positively associated with ovarian cancer (OR = 1.35; 95% CI: 1.05, 1.72; P = 0.017), lung cancer (OR = 1.27; 95% CI: 1.09, 1.49; P = 2.9 × 10(-3)) and colorectal cancer (OR = 1.39; 95% CI: 1.06, 1.82, P = 0.016). The inverse association between genetically predicted adult BMI and breast cancer risk remained even after adjusting for directional pleiotropy via MR-Egger regression.
  
  
  
  Findings from this study provide additional understandings of the complex relationship between adiposity and cancer risks. Our results for breast and lung cancer are particularly interesting, given previous reports of effect heterogeneity by menopausal status and smoking status.
authors.affiliation: Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Chi
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
authors.forename: Chirag J
authors.initials: CJ
authors.lastname: Patel
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK, Department of Electron Microscopy/Molecular Pathology, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus and.
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Michailidou
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Gong
authors.affiliation: Cancer Prevention, Detection & Control Research Program, Duke Cancer Institute, Durham, NC, USA, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
authors.forename: Joellen
authors.initials: J
authors.lastname: Schildkraut
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Fredrick R
authors.initials: FR
authors.lastname: Schumacher
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Tisch Cancer institute and Institute for Transitional Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Boffetta
authors.affiliation: Centre for Research in Epidemiology and Population Health, INSERM, Villejuif, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Stucker
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA, Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Walter
authors.initials: W
authors.lastname: Willett
authors.affiliation: USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gruber
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.affiliation: Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Sellers
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Haiman
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Rayjean J
authors.initials: RJ
authors.lastname: Hung
authors.affiliation: Center for Genomic Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Amos
authors.affiliation: Department of Public Health Studies, University of Chicago, Chicago, IL, USA.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Pierce
authors.affiliation: Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Lindström
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
mesh_terms: D050154:Adiposity / Q000235:genetics*; D015992:Body Mass Index; D001943:Breast Neoplasms / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D057182:Mendelian Randomization Analysis; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016017:Odds Ratio; D010051:Ovarian Neoplasms / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics; D012044:Regression Analysis; D012307:Risk Factors; D049629:Waist-Hip Ratio
keywords: Cancer risk; Mendelian randomization; body mass index; post-GWAS study; waist-to-hip ratio