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 Chong, Richard M Martin, Steve J Thomas, Jessica Tyrrell, Andrew R Ness, Paul Brennan, Marcus R Munafo, Miranda Pring, Stefania Boccia, Andrew F Olshan, Brenda Diergaarde, Rayjean J. Hung, Geoffrey Liu, Eloiza H Tajara, Patricia Severino, Tatiana N ToporcovMartin Lacko, Tim Waterboer, Nicole Brenner, George Davey Smith, Emma E Vincent, Rebecca Richmond

*Corresponding author for this work

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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).

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.

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).

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.
Original languageEnglish
Article number40
JournalBMC Medicine
Issue number1
Publication statusPublished - 31 Jan 2022

Bibliographical note

Funding Information:
M.G. was a National Institute for Health Research (NIHR) academic clinical fellow and is currently supported by a Wellcome Trust GW4-Clinical Academic Training PhD Fellowship. This research was funded in part, by the Wellcome Trust [Grant number 220530/Z/20/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. R.C.R. is a de Pass VC research fellow at the University of Bristol. J.T. is supported by an Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, Global Challenges Research Fund (GCRF), the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK (SBF004\1079). R.M.M. was supported by a Cancer Research UK (C18281/A20919) programme grant (the Integrative Cancer Epidemiology Programme). R.M.M. and A.R.N. are supported by the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre which is funded by the National Institute for Health Research (NIHR) and is a partnership between University Hospitals Bristol NHS Foundation Trust and the University of Bristol. Department of Health and Social Care disclaimer: The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding and the NIHR Senior Investigator award to A.R.N. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (C18281/A20919). B.D. and the University of Pittsburgh head and neck cancer case-control study are supported by US National Institutes of Health (NIH) grants: P50 CA097190, P30 CA047904 and R01 DE025712. The genotyping of the HNSCC cases and controls was performed at the Center for Inherited Disease Research (CIDR) and funded by the US National Institute of Dental and Craniofacial Research (NIDCR; 1X01HG007780-0). The University of North Carolina (UNC) CHANCE study was supported in part by the National Cancer Institute (R01-CA90731). E.E.V is supported by Diabetes UK (17/0005587). E.E.V is also supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). E.H.T and P.S. were supported by FAPESP grant 10/51168-0 (GENCAPO/Head and Neck Genome project). M.G., T.D., K.B., A.C., R.M.M., M.M., G.D.S, E.E.V. and R.C.R are part of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol supported by the Medical Research Council (MC_UU_00011/1, MC_UU_00011/5, MC_UU_00011/6, MC_UU_00011/7).

Publisher Copyright:
© 2022, The Author(s).

Structured keywords

  • ICEP


  • Sexual behaviour
  • Oropharyngeal cancer
  • Head and neck cancer
  • Mendelian randomization


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