title: The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium.
abstract: BACKGROUND
  Epidemiological studies suggest a potential role for obesity and determinants of adult stature in prostate cancer risk and mortality, but the relationships described in the literature are complex. To address uncertainty over the causal nature of previous observational findings, we investigated associations of height- and adiposity-related genetic variants with prostate cancer risk and mortality.
  
  
  METHODS
  We conducted a case-control study based on 20,848 prostate cancers and 20,214 controls of European ancestry from 22 studies in the PRACTICAL consortium. We constructed genetic risk scores that summed each man's number of height and BMI increasing alleles across multiple single nucleotide polymorphisms robustly associated with each phenotype from published genome-wide association studies.
  
  
  RESULTS
  The genetic risk scores explained 6.31 and 1.46% of the variability in height and BMI, respectively. There was only weak evidence that genetic variants previously associated with increased BMI were associated with a lower prostate cancer risk (odds ratio per standard deviation increase in BMI genetic score 0.98; 95% CI 0.96, 1.00; p = 0.07). Genetic variants associated with increased height were not associated with prostate cancer incidence (OR 0.99; 95% CI 0.97, 1.01; p = 0.23), but were associated with an increase (OR 1.13; 95 % CI 1.08, 1.20) in prostate cancer mortality among low-grade disease (p heterogeneity, low vs. high grade <0.001). Genetic variants associated with increased BMI were associated with an increase (OR 1.08; 95 % CI 1.03, 1.14) in all-cause mortality among men with low-grade disease (p heterogeneity = 0.03).
  
  
  CONCLUSIONS
  We found little evidence of a substantial effect of genetically elevated height or BMI on prostate cancer risk, suggesting that previously reported observational associations may reflect common environmental determinants of height or BMI and prostate cancer risk. Genetically elevated height and BMI were associated with increased mortality (prostate cancer-specific and all-cause, respectively) in men with low-grade disease, a potentially informative but novel finding that requires replication.
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK. neil.davies@bristol.ac.uk.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. neil.davies@bristol.ac.uk.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Davies
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
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authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
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authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, BS10 5NB, UK.
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authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
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authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia.
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authors.affiliation: Strangeways Laboratory, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Worts Causeway, Cambridge, UK.
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authors.affiliation: The Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Zsofia
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authors.affiliation: Strangeways Laboratory, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Worts Causeway, Cambridge, UK.
authors.forename: Ali Amin
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authors.affiliation: Strangeways Laboratory, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Worts Causeway, Cambridge, UK.
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authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
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authors.initials: CA
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authors.forename: Johanna
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authors.affiliation: Strangeways Laboratory, Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Worts Causeway, Cambridge, UK.|Department of Applied Health Research, University College London, 1-19 Torrington Place, London, WC1E 7HB, UK.
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authors.affiliation: Cambridge Institute of Public Health, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK.
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authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
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authors.initials: GD
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authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK. richard.martin@bristol.ac.uk.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. richard.martin@bristol.ac.uk.|Bristol Nutrition Biomedical Research Unit, National Institute for Health Research, Bristol, UK. richard.martin@bristol.ac.uk.
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mesh_terms: D050154:Adiposity / Q000235:genetics; D000368:Aged; D000483:Alleles; D001827:Body Height / Q000235:genetics*; D015992:Body Mass Index; D016022:Case-Control Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015994:Incidence; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D009765:Obesity / Q000150:complications; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000453:epidemiology* / Q000235:genetics / Q000401:mortality; D012307:Risk Factors; D044465:White People / Q000235:genetics
keywords: Body mass index; Height; Instrumental variables analysis; Mendelian randomization; Prostate cancer; Single nucleotide polymorphisms