Mark Gormley1,2,3, Tom Dudding4,5,6, Linda Kachuri7, Kimberley Burrows4,6, Amanda H W Chong4,6, Richard M Martin4,6,8, Steven J Thomas5,8, Jessica Tyrrell9, Andrew R Ness8, Paul Brennan10, Marcus R Munafò4,11, Miranda Pring5, Stefania Boccia12,13, Andrew F Olshan14, Brenda Diergaarde15, Rayjean J Hung16,17, Geoffrey Liu17,18, Eloiza H Tajara19, Patricia Severino20, Tatiana N Toporcov21, Martin Lacko22, Tim Waterboer23, Nicole Brenner23, George Davey Smith4,6, Emma E Vincent4,6,24, Rebecca C Richmond4,6. 1. MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. mark.gormley@bristol.ac.uk. 2. Bristol Dental Hospital and School, University of Bristol, Bristol, UK. mark.gormley@bristol.ac.uk. 3. Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. mark.gormley@bristol.ac.uk. 4. MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. 5. Bristol Dental Hospital and School, University of Bristol, Bristol, UK. 6. Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. 7. Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, USA. 8. University Hospitals Bristol and Weston NHS Foundation Trust National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol, Bristol, UK. 9. University of Exeter Medical School, RILD Building, RD&E Hospital, Exeter, UK. 10. Genetic Epidemiology Group, World Health Organization, International Agency for Research on Cancer, Lyon, France. 11. School of Psychological Science, Faculty of Life Sciences, University of Bristol, Bristol, UK. 12. Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Roma, Italia. 13. Department of Woman and Child Health and Public Health - Public Health Area, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy. 14. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, USA. 15. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, and UPMC Hillman Cancer Center, Pittsburgh, USA. 16. Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada. 17. Dalla Lana School of Public Health, University of Toronto, Toronto, Canada. 18. Princess Margaret Cancer Centre, Toronto, Canada. 19. Department of Molecular Biology, School of Medicine of São José do Rio Preto, São Paulo, Brazil. 20. Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, Brazil. 21. Department of Epidemiology, School of Public Health, University of São Paulo, São Paulo, Brazil. 22. Department of Otorhinolaryngology and Head and Neck Surgery, Research Institute GROW, Maastricht University Medical Center, Maastricht, The Netherlands. 23. Infections and Cancer Epidemiology, Deutsches Krebsforschungszentrum, Heidelberg, Germany. 24. School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
Abstract
BACKGROUND: Human papilloma virus infection is known to influence oropharyngeal cancer (OPC) risk, likely via sexual transmission. However, sexual behaviour has been correlated with other risk factors including smoking and alcohol, meaning independent effects are difficult to establish. We aimed to evaluate the causal effect of sexual behaviour on the risk of OPC using Mendelian randomization (MR). METHODS: Genetic variants robustly associated with age at first sex (AFS) and the number of sexual partners (NSP) were used to perform both univariable and multivariable MR analyses with summary data on 2641 OPC cases and 6585 controls, obtained from the largest available genome-wide association studies (GWAS). Given the potential for genetic pleiotropy, we performed a number of sensitivity analyses: (i) MR methods to account for horizontal pleiotropy, (ii) MR of sexual behaviours on positive (cervical cancer and seropositivity for Chlamydia trachomatis) and negative control outcomes (lung and oral cancer), (iii) Causal Analysis Using Summary Effect estimates (CAUSE), to account for correlated and uncorrelated horizontal pleiotropic effects, (iv) multivariable MR analysis to account for the effects of smoking, alcohol, risk tolerance and educational attainment. RESULTS: In univariable MR, we found evidence supportive of an effect of both later AFS (IVW OR = 0.4, 95%CI (0.3, 0.7), per standard deviation (SD), p = < 0.001) and increasing NSP (IVW OR = 2.2, 95%CI (1.3, 3.8) per SD, p = < 0.001) on OPC risk. These effects were largely robust to sensitivity analyses accounting for horizontal pleiotropy. However, negative control analysis suggested potential violation of the core MR assumptions and subsequent CAUSE analysis implicated pleiotropy of the genetic instruments used to proxy sexual behaviours. Finally, there was some attenuation of the univariable MR results in the multivariable models (AFS IVW OR = 0.7, 95%CI (0.4, 1.2), p = 0.21; NSP IVW OR = 0.9, 95%CI (0.5 1.7), p = 0.76). CONCLUSIONS: Despite using genetic variants strongly related sexual behaviour traits in large-scale GWAS, we found evidence for correlated pleiotropy. This emphasizes a need for multivariable approaches and the triangulation of evidence when performing MR of complex behavioural traits.
BACKGROUND: Human papilloma virus infection is known to influence oropharyngeal cancer (OPC) risk, likely via sexual transmission. However, sexual behaviour has been correlated with other risk factors including smoking and alcohol, meaning independent effects are difficult to establish. We aimed to evaluate the causal effect of sexual behaviour on the risk of OPC using Mendelian randomization (MR). METHODS: Genetic variants robustly associated with age at first sex (AFS) and the number of sexual partners (NSP) were used to perform both univariable and multivariable MR analyses with summary data on 2641 OPC cases and 6585 controls, obtained from the largest available genome-wide association studies (GWAS). Given the potential for genetic pleiotropy, we performed a number of sensitivity analyses: (i) MR methods to account for horizontal pleiotropy, (ii) MR of sexual behaviours on positive (cervical cancer and seropositivity for Chlamydia trachomatis) and negative control outcomes (lung and oral cancer), (iii) Causal Analysis Using Summary Effect estimates (CAUSE), to account for correlated and uncorrelated horizontal pleiotropic effects, (iv) multivariable MR analysis to account for the effects of smoking, alcohol, risk tolerance and educational attainment. RESULTS: In univariable MR, we found evidence supportive of an effect of both later AFS (IVW OR = 0.4, 95%CI (0.3, 0.7), per standard deviation (SD), p = < 0.001) and increasing NSP (IVW OR = 2.2, 95%CI (1.3, 3.8) per SD, p = < 0.001) on OPC risk. These effects were largely robust to sensitivity analyses accounting for horizontal pleiotropy. However, negative control analysis suggested potential violation of the core MR assumptions and subsequent CAUSE analysis implicated pleiotropy of the genetic instruments used to proxy sexual behaviours. Finally, there was some attenuation of the univariable MR results in the multivariable models (AFS IVW OR = 0.7, 95%CI (0.4, 1.2), p = 0.21; NSP IVW OR = 0.9, 95%CI (0.5 1.7), p = 0.76). CONCLUSIONS: Despite using genetic variants strongly related sexual behaviour traits in large-scale GWAS, we found evidence for correlated pleiotropy. This emphasizes a need for multivariable approaches and the triangulation of evidence when performing MR of complex behavioural traits.
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Authors: Aimée R Kreimer; Mattias Johansson; Tim Waterboer; Rudolf Kaaks; Jenny Chang-Claude; Dagmar Drogen; Anne Tjønneland; Kim Overvad; J Ramón Quirós; Carlos A González; Maria José Sánchez; Nerea Larrañaga; Carmen Navarro; Aurelio Barricarte; Ruth C Travis; Kay-Tee Khaw; Nick Wareham; Antonia Trichopoulou; Pagona Lagiou; Dimitrios Trichopoulos; Petra H M Peeters; Salvatore Panico; Giovanna Masala; Sara Grioni; Rosario Tumino; Paolo Vineis; H Bas Bueno-de-Mesquita; Göran Laurell; Göran Hallmans; Jonas Manjer; Johanna Ekström; Guri Skeie; Eiliv Lund; Elisabete Weiderpass; Pietro Ferrari; Graham Byrnes; Isabelle Romieu; Elio Riboli; Allan Hildesheim; Heiner Boeing; Michael Pawlita; Paul Brennan Journal: J Clin Oncol Date: 2013-06-17 Impact factor: 44.544