Reassessing the link between adiposity and head and neck cancer: a Mendelian randomization study

Fernanda Morales Berstein; Jasmine Khouja; Mark Gormley; Elmira Ebrahimi; Shama Virani; James D McKay; Paul Brennan; Tom G Richardson; Caroline L Relton; George Davey Smith; M Carolina Borges; Tom Dudding; Rebecca C Richmond

doi:10.7554/eLife.106075

Reassessing the link between adiposity and head and neck cancer: a Mendelian randomization study

Fernanda Morales Berstein
, Jasmine Khouja
, Mark Gormley
, Elmira Ebrahimi
, Shama Virani
, James D McKay
, Paul Brennan
, Tom G Richardson
, Caroline L Relton
, George Davey Smith
, M Carolina Borges
, Tom Dudding
, Rebecca C Richmond

Department of Psychology

University of Bristol
MRC Integrative Epidemiology Unit
Genomic Epidemiology Branch

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

Abstract

BACKGROUND: Adiposity has been associated with an increased risk of head and neck cancer (HNC). Although body mass index (BMI) has been inversely associated with HNC risk among smokers, this is likely due to confounding. Previous Mendelian randomization (MR) studies could not fully discount causality between adiposity and HNC. Hence, we aimed to revisit this using the largest genome-wide association study (GWAS) of HNC available, which has more granular data on HNC subsites.

METHODS: We assessed the genetically predicted effects of BMI (N=806,834), waist-to-hip ratio (WHR; N=697,734) and waist circumference (N=462,166) on the risk of HNC (N=12,264 cases) and its subsites using a two-sample MR framework. We used inverse variance weighted (IVW) MR and multiple sensitivity analyses, including multivariable MR (MVMR), to explore the direct effects of the adiposity measures on HNC, while accounting for smoking behaviour (a well-known HNC risk factor).

RESULTS: In univariable MR, higher genetically predicted BMI increased the risk of overall HNC (IVW OR = 1.17 per 1-SD higher BMI, 95% CI 1.02-1.34). However, the IVW effect was attenuated when smoking was included in the MVMR model (OR accounting for comprehensive smoking index = 0.96 per 1-SD higher BMI, 95% CI 0.80-1.15). Furthermore, we did not find a link between genetically predicted WHR (IVW OR = 1.05 per 1-SD higher WHR, 95% CI 0.89-1.24) or waist circumference and HNC risk (IVW OR = 1.01 per 1-SD higher waist circumference, 95% CI 0.85-1.21).

CONCLUSIONS: Our findings suggest that adiposity does not play a major role in HNC risk.

FUNDING: FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z). RCR was supported by a Cancer Research UK grant (C18281/A29019). MCB is supported by a University of Bristol Vice Chancellor's Fellowship, the British Heart Foundation (AA/18/1/34219) and the UK Medical Research Council (MC_UU_00032/5). GDS works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00032/1). CLR was supported by the Medical Research Council (MC_UU_00011/5) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). SV was funded by an EU Horizon 2020 grant (agreement number 825771) and NIDCR National Institutes of Dental and Craniofacial Health (R03DE030257). JK works in a unit that receives support from the University of Bristol, a Cancer Research UK grant (C18281/A29019) and the UK Medical Research Council (grant number: MC_UU_00032/7).

Original language	English
Journal	eLife
Volume	14
DOIs	https://doi.org/10.7554/eLife.106075
Publication status	Published - 9 Oct 2025

Bibliographical note

Data Availability Statement

All the GWAS datasets used in our study are publicly available. The GWAS summary statistics for waist circumference are available via the IEU OpenGWAS platform (id: ukb-b-9405). The GWAS summary statistics for BMI and WHR by Pulit et al., 2019 can be downloaded from https://zenodo.org/records/1251813. The data sources for the other adiposity-related measures have been specified in Table 1. The smoking behaviour traits GWAS data were downloaded from https://data.bris.ac.uk/data/dataset/10i96zb8gm0j81yz0q6ztei23d (for CSI) and https://doi.org/10.13020/przg-dp88 (for smoking initiation). The outcome datasets used in our analyses have been uploaded to the IEU OpenGWAS project platform for reproducibility. However, because the data was originally in build GRCh38, some multiallelic SNPs that could not be aligned with GRCh37 Human Genome reference sequence were dropped when lifting the data to build HG19/GRCh37 (which was required at the time of upload: April 2024). The following IEU OpenGWAS id's were assigned to the European HEADSpAcE HNC GWAS datasets including/excluding UK Biobank: ieu-b-5129/ieu-b-5123 for overall HNC, ieu-b-5132/ieu-b-5126 for oral cavity cancer, ieu-b-5130/ieu-b-5124 for hypopharynx cancer, ieu-b-5134/ieu-b-5128 for HPV positive oropharynx cancer, ieu-b-5133/ieu-b-5127 for HPV negative oropharynx cancer, and ieu-b-5131/ieu-b-5125 for larynx cancer. The R code used to run the MR analyses is available at https://github.com/fernandam93/adiposity_HNC_MR (copy archived at Morales Berstein, 2025).

Funding

We thank Richard Wilkinson for proofreading several versions of the manuscript. We would also like to thank Weili (Jason) Qiu, the IEU Data Manager, for his help debugging code and uploading the HNC GWAS summary statistics to the IEU OpenGWAS platform. FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z). RCR was supported by a Cancer Research UK grant (C18281/A29019). MCB is supported by a University of Bristol Vice Chancellor’s Fellowship, the British Heart Foundation (AA/18/1/34219) and the UK Medical Research Council (MC_UU_00032/5). GDS works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00032/1). CLR was supported by the Medical Research Council (MC_UU_00011/5) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). SV was funded by an EU Horizon 2020 grant (agreement number 825771) and NIDCR National Institutes of Dental and Craniofacial Health (R03DE030257). JK works in a unit that receives support from the University of Bristol, a Cancer Research UK grant (C18281/A29019) and the UK Medical Research Council (grant number: MC_UU_00032/7).

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Humans
Mendelian Randomization Analysis
Adiposity/genetics
Head and Neck Neoplasms/genetics
Body Mass Index
Genome-Wide Association Study
Male
Female
Risk Factors
Middle Aged
Waist-Hip Ratio
Waist Circumference
Aged
Adult

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10.7554/eLife.106075Licence: CC BY

Cite this

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title = "Reassessing the link between adiposity and head and neck cancer: a Mendelian randomization study",

abstract = "BACKGROUND: Adiposity has been associated with an increased risk of head and neck cancer (HNC). Although body mass index (BMI) has been inversely associated with HNC risk among smokers, this is likely due to confounding. Previous Mendelian randomization (MR) studies could not fully discount causality between adiposity and HNC. Hence, we aimed to revisit this using the largest genome-wide association study (GWAS) of HNC available, which has more granular data on HNC subsites.METHODS: We assessed the genetically predicted effects of BMI (N=806,834), waist-to-hip ratio (WHR; N=697,734) and waist circumference (N=462,166) on the risk of HNC (N=12,264 cases) and its subsites using a two-sample MR framework. We used inverse variance weighted (IVW) MR and multiple sensitivity analyses, including multivariable MR (MVMR), to explore the direct effects of the adiposity measures on HNC, while accounting for smoking behaviour (a well-known HNC risk factor).RESULTS: In univariable MR, higher genetically predicted BMI increased the risk of overall HNC (IVW OR = 1.17 per 1-SD higher BMI, 95\% CI 1.02-1.34). However, the IVW effect was attenuated when smoking was included in the MVMR model (OR accounting for comprehensive smoking index = 0.96 per 1-SD higher BMI, 95\% CI 0.80-1.15). Furthermore, we did not find a link between genetically predicted WHR (IVW OR = 1.05 per 1-SD higher WHR, 95\% CI 0.89-1.24) or waist circumference and HNC risk (IVW OR = 1.01 per 1-SD higher waist circumference, 95\% CI 0.85-1.21).CONCLUSIONS: Our findings suggest that adiposity does not play a major role in HNC risk.FUNDING: FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z). RCR was supported by a Cancer Research UK grant (C18281/A29019). MCB is supported by a University of Bristol Vice Chancellor's Fellowship, the British Heart Foundation (AA/18/1/34219) and the UK Medical Research Council (MC\_UU\_00032/5). GDS works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC\_UU\_00032/1). CLR was supported by the Medical Research Council (MC\_UU\_00011/5) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). SV was funded by an EU Horizon 2020 grant (agreement number 825771) and NIDCR National Institutes of Dental and Craniofacial Health (R03DE030257). JK works in a unit that receives support from the University of Bristol, a Cancer Research UK grant (C18281/A29019) and the UK Medical Research Council (grant number: MC\_UU\_00032/7).",

keywords = "Humans, Mendelian Randomization Analysis, Adiposity/genetics, Head and Neck Neoplasms/genetics, Body Mass Index, Genome-Wide Association Study, Male, Female, Risk Factors, Middle Aged, Waist-Hip Ratio, Waist Circumference, Aged, Adult",

author = "\{Morales Berstein\}, Fernanda and Jasmine Khouja and Mark Gormley and Elmira Ebrahimi and Shama Virani and McKay, \{James D\} and Paul Brennan and Richardson, \{Tom G\} and Relton, \{Caroline L\} and \{Davey Smith\}, George and Borges, \{M Carolina\} and Tom Dudding and Richmond, \{Rebecca C\}",

note = "{\textcopyright} 2025, Morales Berstein et al.",

year = "2025",

month = oct,

day = "9",

doi = "10.7554/eLife.106075",

language = "English",

volume = "14",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications Ltd",

}

TY - JOUR

T1 - Reassessing the link between adiposity and head and neck cancer

T2 - a Mendelian randomization study

AU - Morales Berstein, Fernanda

AU - Khouja, Jasmine

AU - Gormley, Mark

AU - Ebrahimi, Elmira

AU - Virani, Shama

AU - McKay, James D

AU - Brennan, Paul

AU - Richardson, Tom G

AU - Relton, Caroline L

AU - Davey Smith, George

AU - Borges, M Carolina

AU - Dudding, Tom

AU - Richmond, Rebecca C

PY - 2025/10/9

Y1 - 2025/10/9

N2 - BACKGROUND: Adiposity has been associated with an increased risk of head and neck cancer (HNC). Although body mass index (BMI) has been inversely associated with HNC risk among smokers, this is likely due to confounding. Previous Mendelian randomization (MR) studies could not fully discount causality between adiposity and HNC. Hence, we aimed to revisit this using the largest genome-wide association study (GWAS) of HNC available, which has more granular data on HNC subsites.METHODS: We assessed the genetically predicted effects of BMI (N=806,834), waist-to-hip ratio (WHR; N=697,734) and waist circumference (N=462,166) on the risk of HNC (N=12,264 cases) and its subsites using a two-sample MR framework. We used inverse variance weighted (IVW) MR and multiple sensitivity analyses, including multivariable MR (MVMR), to explore the direct effects of the adiposity measures on HNC, while accounting for smoking behaviour (a well-known HNC risk factor).RESULTS: In univariable MR, higher genetically predicted BMI increased the risk of overall HNC (IVW OR = 1.17 per 1-SD higher BMI, 95% CI 1.02-1.34). However, the IVW effect was attenuated when smoking was included in the MVMR model (OR accounting for comprehensive smoking index = 0.96 per 1-SD higher BMI, 95% CI 0.80-1.15). Furthermore, we did not find a link between genetically predicted WHR (IVW OR = 1.05 per 1-SD higher WHR, 95% CI 0.89-1.24) or waist circumference and HNC risk (IVW OR = 1.01 per 1-SD higher waist circumference, 95% CI 0.85-1.21).CONCLUSIONS: Our findings suggest that adiposity does not play a major role in HNC risk.FUNDING: FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z). RCR was supported by a Cancer Research UK grant (C18281/A29019). MCB is supported by a University of Bristol Vice Chancellor's Fellowship, the British Heart Foundation (AA/18/1/34219) and the UK Medical Research Council (MC_UU_00032/5). GDS works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00032/1). CLR was supported by the Medical Research Council (MC_UU_00011/5) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). SV was funded by an EU Horizon 2020 grant (agreement number 825771) and NIDCR National Institutes of Dental and Craniofacial Health (R03DE030257). JK works in a unit that receives support from the University of Bristol, a Cancer Research UK grant (C18281/A29019) and the UK Medical Research Council (grant number: MC_UU_00032/7).

AB - BACKGROUND: Adiposity has been associated with an increased risk of head and neck cancer (HNC). Although body mass index (BMI) has been inversely associated with HNC risk among smokers, this is likely due to confounding. Previous Mendelian randomization (MR) studies could not fully discount causality between adiposity and HNC. Hence, we aimed to revisit this using the largest genome-wide association study (GWAS) of HNC available, which has more granular data on HNC subsites.METHODS: We assessed the genetically predicted effects of BMI (N=806,834), waist-to-hip ratio (WHR; N=697,734) and waist circumference (N=462,166) on the risk of HNC (N=12,264 cases) and its subsites using a two-sample MR framework. We used inverse variance weighted (IVW) MR and multiple sensitivity analyses, including multivariable MR (MVMR), to explore the direct effects of the adiposity measures on HNC, while accounting for smoking behaviour (a well-known HNC risk factor).RESULTS: In univariable MR, higher genetically predicted BMI increased the risk of overall HNC (IVW OR = 1.17 per 1-SD higher BMI, 95% CI 1.02-1.34). However, the IVW effect was attenuated when smoking was included in the MVMR model (OR accounting for comprehensive smoking index = 0.96 per 1-SD higher BMI, 95% CI 0.80-1.15). Furthermore, we did not find a link between genetically predicted WHR (IVW OR = 1.05 per 1-SD higher WHR, 95% CI 0.89-1.24) or waist circumference and HNC risk (IVW OR = 1.01 per 1-SD higher waist circumference, 95% CI 0.85-1.21).CONCLUSIONS: Our findings suggest that adiposity does not play a major role in HNC risk.FUNDING: FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z). RCR was supported by a Cancer Research UK grant (C18281/A29019). MCB is supported by a University of Bristol Vice Chancellor's Fellowship, the British Heart Foundation (AA/18/1/34219) and the UK Medical Research Council (MC_UU_00032/5). GDS works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00032/1). CLR was supported by the Medical Research Council (MC_UU_00011/5) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). SV was funded by an EU Horizon 2020 grant (agreement number 825771) and NIDCR National Institutes of Dental and Craniofacial Health (R03DE030257). JK works in a unit that receives support from the University of Bristol, a Cancer Research UK grant (C18281/A29019) and the UK Medical Research Council (grant number: MC_UU_00032/7).

KW - Humans

KW - Mendelian Randomization Analysis

KW - Adiposity/genetics

KW - Head and Neck Neoplasms/genetics

KW - Body Mass Index

KW - Genome-Wide Association Study

KW - Male

KW - Female

KW - Risk Factors

KW - Middle Aged

KW - Waist-Hip Ratio

KW - Waist Circumference

KW - Aged

KW - Adult

U2 - 10.7554/eLife.106075

DO - 10.7554/eLife.106075

M3 - Article

C2 - 41065334

SN - 2050-084X

VL - 14

JO - eLife

JF - eLife

ER -

Reassessing the link between adiposity and head and neck cancer: a Mendelian randomization study

Abstract

Bibliographical note

Data Availability Statement

Funding

UN SDGs

Keywords

Access to Document

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Cite this