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

doi:10.1186/s12916-022-02233-3

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. ToporcovMartin Lacko, Tim Waterboer, Nicole Brenner, George Davey Smith, Emma E. Vincent, Rebecca C. Richmond

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	40
Journal	BMC medicine
Volume	20
Issue number	1
DOIs	https://doi.org/10.1186/s12916-022-02233-3
Publication status	Published - 31 Jan 2022

Data Availability Statement

Summary-level analysis was conducted using publicly available GWAS data. Full summary statistics for the GAME-ON outcome data GWAS can be accessed via dbGAP (OncoArray: Oral and Pharynx Cancer; study accession number: phs001202.v1.p1, August 2017 at: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001202.v1.p1) [82]. There is one selected publication by Lesseur et al. related to this data [31].

Lung cancer GWAS data is available via dbGAP (Transdisciplinary Research Into Cancer of the Lung (TRICL) - Meta Analysis; dbGaP study accession number: phs000877.v1.p1, March 2015 at: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000877.v1.p1) [83], with three selected publications relevant to this study [48, 84, 85].

Summary-level data for the main exposures used in this study were derived from the relevant publications for age at first sex [28] and number of sexual partners [26], smoking initiation, 60 SNPs for alcoholic drinks per week [51], comprehensive smoking index [53], 123 for risk tolerance [26], and 317 SNPs for educational attainment [52]. Cervical cancer, HPV and C. trachomatis GWAS data were all derived using UK Biobank as described. Access to UK Biobank (https://www.ukbiobank.ac.uk/) data is available to researchers through application and is described in the relevant publication by Bycroft et al. [30]. UK Biobank approval was given for this project (ID 40644 “Investigating aetiology, associations and causality in diseases of the head and neck”) and UK Biobank GWAS data was also accessed under the application (ID 15825 “MR-Base: an online resource for Mendelian randomization using summary data”- Dr Philip Haycock).” Genetic instruments derived from UK Biobank may also be available via the IEU OpenGWAS project (https://gwas.mrcieu.ac.uk/) with relevant publications to support this resource from Elsworth et al. [86] and Hemani et al. [87]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

MR analyses were conducted using the “TwoSampleMR” package in R (version 3.5.3). A copy of the code and all files used in this analysis is available at GitHub [88] via https://github.com/rcrichmond/sexual_behaviours_opc.

Keywords

Head and neck cancer
Mendelian randomization
Oropharyngeal cancer
Sexual behaviour

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Gormley, M., Dudding, T., Kachuri, L., Burrows, K., Chong, A. H. W., Martin, R. M., Thomas, S. J., Tyrrell, J., Ness, A. R., Brennan, P., Munafò, M. R., Pring, M., Boccia, S., Olshan, A. F., Diergaarde, B., Hung, R. J., Liu, G., Tajara, E. H., Severino, P., ... Richmond, R. C. (2022). Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization. BMC medicine, 20(1), Article 40. https://doi.org/10.1186/s12916-022-02233-3

Gormley, M, Dudding, T, Kachuri, L, Burrows, K, Chong, AHW, Martin, RM, Thomas, SJ, Tyrrell, J, Ness, AR, Brennan, P, Munafò, MR, Pring, M, Boccia, S, Olshan, AF, Diergaarde, B, Hung, RJ, Liu, G, Tajara, EH, Severino, P, Toporcov, TN, Lacko, M, Waterboer, T, Brenner, N, Smith, GD, Vincent, EE & Richmond, RC 2022, 'Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization', BMC medicine, vol. 20, no. 1, 40. https://doi.org/10.1186/s12916-022-02233-3

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title = "Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization",

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.",

keywords = "Head and neck cancer, Mendelian randomization, Oropharyngeal cancer, Sexual behaviour",

author = "Mark Gormley and Tom Dudding and Linda Kachuri and Kimberley Burrows and Chong, {Amanda H.W.} and Martin, {Richard M.} and Thomas, {Steven J.} and Jessica Tyrrell and Ness, {Andrew R.} and Paul Brennan and Munaf{\`o}, {Marcus R.} and Miranda Pring and Stefania Boccia and Olshan, {Andrew F.} and Brenda Diergaarde and Hung, {Rayjean J.} and Geoffrey Liu and Tajara, {Eloiza H.} and Patricia Severino and Toporcov, {Tatiana N.} and Martin Lacko and Tim Waterboer and Nicole Brenner and Smith, {George Davey} and Vincent, {Emma E.} and Richmond, {Rebecca C.}",

year = "2022",

month = jan,

day = "31",

doi = "10.1186/s12916-022-02233-3",

language = "English",

volume = "20",

journal = "BMC medicine",

issn = "1741-7015",

publisher = "BioMed Central",

number = "1",

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TY - JOUR

T1 - Investigating the effect of sexual behaviour on oropharyngeal cancer risk

T2 - a methodological assessment of Mendelian randomization

AU - Gormley, Mark

AU - Dudding, Tom

AU - Kachuri, Linda

AU - Burrows, Kimberley

AU - Chong, Amanda H.W.

AU - Martin, Richard M.

AU - Thomas, Steven J.

AU - Tyrrell, Jessica

AU - Ness, Andrew R.

AU - Brennan, Paul

AU - Munafò, Marcus R.

AU - Pring, Miranda

AU - Boccia, Stefania

AU - Olshan, Andrew F.

AU - Diergaarde, Brenda

AU - Hung, Rayjean J.

AU - Liu, Geoffrey

AU - Tajara, Eloiza H.

AU - Severino, Patricia

AU - Toporcov, Tatiana N.

AU - Lacko, Martin

AU - Waterboer, Tim

AU - Brenner, Nicole

AU - Smith, George Davey

AU - Vincent, Emma E.

AU - Richmond, Rebecca C.

PY - 2022/1/31

Y1 - 2022/1/31

N2 - 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.

AB - 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.

KW - Head and neck cancer

KW - Mendelian randomization

KW - Oropharyngeal cancer

KW - Sexual behaviour

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U2 - 10.1186/s12916-022-02233-3

DO - 10.1186/s12916-022-02233-3

M3 - Article

AN - SCOPUS:85124008849

SN - 1741-7015

VL - 20

JO - BMC medicine

JF - BMC medicine

IS - 1

M1 - 40

ER -

Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization

Abstract

Data Availability Statement

Keywords

ASJC Scopus subject areas

UN SDGs

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