Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization
Mark Gormley,
Tom Dudding,
Linda Kachuri,
Kimberley Burrows,
Amanda H. W. Chong,
Richard M. Martin,
Steven J. Thomas,
Jessica Tyrrell,
Andrew R. Ness,
Paul Brennan,
Marcus R. Munafò,
Miranda Pring,
Stefania Boccia,
Andrew F. Olshan,
Brenda Diergaarde,
Rayjean J. Hung,
Geoffrey Liu,
Eloiza H. Tajara,
Patricia Severino,
Tatiana N. Toporcov,
Martin Lacko,
Tim Waterboer,
Nicole Brenner,
George Davey Smith,
Emma E. Vincent,
Rebecca C. Richmond
Affiliations
Mark Gormley
MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol
Tom Dudding
MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol
Linda Kachuri
Department of Epidemiology & Biostatistics, University of California San Francisco
Kimberley Burrows
MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol
Amanda H. W. Chong
MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol
Richard M. Martin
MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol
Steven J. Thomas
Bristol Dental Hospital and School, University of Bristol
Jessica Tyrrell
University of Exeter Medical School, RILD Building, RD&E Hospital
Andrew R. Ness
University Hospitals Bristol and Weston NHS Foundation Trust National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol
Paul Brennan
Genetic Epidemiology Group, World Health Organization, International Agency for Research on Cancer
Marcus R. Munafò
MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol
Miranda Pring
Bristol Dental Hospital and School, University of Bristol
Stefania Boccia
Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore
Andrew F. Olshan
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina
Brenda Diergaarde
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, and UPMC Hillman Cancer Center
Rayjean J. Hung
Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System
Geoffrey Liu
Dalla Lana School of Public Health, University of Toronto
Eloiza H. Tajara
Department of Molecular Biology, School of Medicine of São José do Rio Preto
Patricia Severino
Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein
Tatiana N. Toporcov
Department of Epidemiology, School of Public Health, University of São Paulo
Martin Lacko
Department of Otorhinolaryngology and Head and Neck Surgery, Research Institute GROW, Maastricht University Medical Center
Tim Waterboer
Infections and Cancer Epidemiology, Deutsches Krebsforschungszentrum
Nicole Brenner
Infections and Cancer Epidemiology, Deutsches Krebsforschungszentrum
George Davey Smith
MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol
Emma E. Vincent
MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol
Rebecca C. Richmond
MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol
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.
