Reassessing the link between adiposity and head and neck cancer: a Mendelian randomization study
- MRC Integrative Epidemiology Unit, University of Bristol, United Kingdom
- Population Health Sciences, Bristol Medical School, University of Bristol, United Kingdom
- University of Bristol Dental School, United Kingdom
- Genomic Epidemiology Branch, International Agency for Research on Cancer, World Health Organization, France
- London School of Hygiene & Tropical Medicine, United Kingdom
Figures
Figure 1
Flowchart summarising the two-sample MR framework used in this study.
Figure 2
Forest plot for the genetically predicted effects of body mass index on the risk of head and neck cancer and its subsites.
Figure 3
Forest plot for the genetically predicted effects of waist-to-hip ratio on the risk of head and neck cancer and its subsites.
Figure 4
Forest plot for the genetically predicted effects of waist circumference on the risk of head and neck cancer and its subsites.
Figure 5
Forest plot for the genetically predicted effects of BMI on the risk of HNC and its subsites, before (univariable-black) and after (multivariable-blue) accounting for comprehensive smoking index (CSI).
Figure 6
Forest plot for the genetically predicted effects of BMI on the risk of HNC and its subsites, before (univariable-black) and after (multivariable-blue) accounting for smoking initiation (SI).
Appendix 1—figure 1
Power calculations for HEADSpAcE head and neck cancer risk.
Minimum odds ratios for body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) were estimated assuming an alpha value of 0.05, power of 80% and total variances (R2) of 4.8%, 3.1%, and 4.4%, respectively.
Appendix 1—figure 2
Power calculation plot for GAME-ON oral cancer and oropharyngeal cancer risk.
Minimum odds ratios for body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) were estimated assuming an alpha value of 0.05, power of 80% and total variances (R2) of 4.8%, 3.1%, and 4.4%, respectively.
Appendix 1—figure 3
Scatter plot for the genetically predicted effects of body mass index (BMI) on the risk of head and neck cancer (HNC).
Appendix 1—figure 4
Scatter plot for the genetically predicted effects of waist-to-hip ratio (WHR) on the risk of head and neck cancer (HNC).
Appendix 1—figure 5
Scatter plot for the genetically predicted effects of waist circumference (WC) on the risk of head and neck cancer (HNC).
Appendix 1—figure 6
CAUSE analysis for the genetically predicted effect of body mass index (BMI) on head and neck cancer (HNC) risk.
CAUSE estimates for HNC reported per 1-SD higher BMI in log odds ratio scale. The ELPD Contribution plot shows the relative contribution of each SNP to the CAUSE test statistic. Only SNPs with p<5e-8 are shown. SNPs represented by larger circles reflect smaller p-values for the associations between genetic variants and BMI. SNPs that contribute more to the causal model are shown in warmer tones (i.e. red), while those that contribute more to the sharing model are shown in colder tones (i.e. blue). The delta_elpd is the statistic used to compare models. It is equal to elpd(model 1)- elpd(model 2). In the table on the left, negative delta_elpd’s suggest that model 2 is a better fit to the data than model 1 (i.e. that the sharing model is better than the null model in row 1, that the causal model is better than the null model in row 2, and that the causal model is better than the sharing model in row 3). The corresponding p-values test whether model 2 is a better fit than model 1. Here, row 3 suggests that the causal model is not a much better fit than the sharing model (the delta_elpd is negative but the p-value is 0.47, so there is no overwhelming evidence against the null hypothesis that the causal model is better than the sharing model). In the table on the right, eta represents the sharing factor effect (SNPs affect shared factor and shared factor simultaneously affects BMI and HNC) and gamma represents the causal factor effect (SNPs affect BMI and BMI affects HNC). Here, ‘0.11 (-0.07, 0.29)’ represents the genetically predicted effect of BMI on HNC after adjusting for correlated and uncorrelated horizontal pleiotropy (results in log odds ratio scale). The intervals shown are credible intervals.
Appendix 1—figure 7
Scatter plots depicting clusters of genetic associations with body mass index (BMI) and head and neck cancer (HNC), before (A) and after (B) conditional probability filtering.
Appendix 1—figure 8
Forest plots for the genetically predicted effects of four body shape principal components (PCs) on the risk of head and neck cancer and its subsites, where (A) PC1 is a measure of overall adiposity, (B) PC2 is a measure of tall and slim vs short and plump, (C) PC3 is a measure of tall with small hip vs short with big hip and (D) PC4 is a measure of high body mass index (BMI) and weight with small hip and waist vs low BMI and weight with big hip and waist.
Appendix 1—figure 9
Forest plots for the genetically predicted effects of (A) childhood and (B) adulthood body size on the risk of head and neck cancer and its subsites.
Appendix 1—figure 10
Forest plots for the genetically predicted effects of (A) favourable and (B) unfavourable adiposity on the risk of head and neck cancer and its subsites.
Appendix 1—figure 11
Forest plots for the genetically predicted effect of body fat percentage on the risk of head and neck cancer and its subsites.
Appendix 1—figure 12
Forest plots for genetically predicted effects of (A) adipose and (B) brain tissue-specific body mass index (BMI) on head and neck cancer and its subsites.
Tables
Table 1
Data sources and instruments for other adiposity-related anthropometric measures.
| Study | Year | Data source | Trait | Unit | Download link or OpenGWAS ID |
|---|---|---|---|---|---|
| Ried et al., 2016 | 2016 | GIANT | Body shape PC1 (overall adiposity) | SD | https://www.joelhirschhornlab.org/giant-consortium-results |
| Body shape PC2 (tall and slim vs short and plump) | SD | ||||
| Body shape PC3 (tall with small hip vs short with big hip) | SD | ||||
| Body shape PC4 (high BMI and weight with small hip and waist vs low BMI and weight with big hip and waist) | SD | ||||
| Richardson et al., 2020 | 2020 | UKB | Childhood body size | Change in body size category | ‘ieu-b-5107’ |
| Adulthood body size | Change in body size category | ‘ieu-b-5118’ | |||
| Martin et al., 2021 | 2021 | UKB | Metabolically favourable adiposity | SD | https://doi.org/10.2337/figshare.14555463.v1 |
| Metabolically unfavourable adiposity | SD | ||||
| MRC-IEU (Elsworth) | 2018 | UKB | Body fat percentage | SD | ‘ukb-b-8909’ |
| Leyden et al., 2022 | 2022 | GIANT +UKB | Brain tissue-specific BMI | SD | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8874216/bin/mmc2.xlsx |
| Adipose tissue-specific BMI | SD |
-
BMI, body mass index; GIANT, Genetic Investigation of Anthropometric Traits; N, number; PC, principal component; SD, standard deviation; SNP, single-nucleotide polymorphism; UKB, UK Biobank.
Table 2
F-statistics and variance explained for other adiposity-related anthropometric measures.
| Trait | N SNPs before/after harmonisation | Total R2 | Mean F-statistics (range) |
|---|---|---|---|
| Body shape PC1 (overall adiposity) | 29/28 | 16% | 54 (28–302) |
| Body shape PC2 (tall and slim vs short and plump) | 84/81 | 3.4% | 54 (30–211) |
| Body shape PC3 (tall with small hip vs short with big hip) | 28/27 | 0.9% | 41 (30–82) |
| Body shape PC4 (high BMI and weight with small hip and waist vs low BMI and weight with big hip and waist) | 10/10 | 24.7% | 42 (30–98) |
| Childhood body size | 206/198 | 3.4% | 78 (28–1102) |
| Adulthood body size | 339/324 | 4.2% | 59 (30–1109) |
| Metabolically favourable adiposity | 34/31 | 0.4% | 64 (25–400) |
| Metabolically unfavourable adiposity | 29/27 | 0.8% | 131 (25–400) |
| Body fat percentage | 377/360 | 4.7% | 59 (30–682) |
| Brain tissue-specific BMI | 140/133 | 1.2% | 61 (29–270) |
| Adipose tissue-specific BMI | 86/81 | 0.7% | 63 (30–270) |
-
BMI, body mass index; N, number; PC, principal component; SNP, single-nucleotide polymorphism.
Additional files
-
Supplementary file 1
Supplementary Tables A to N.
- https://cdn.elifesciences.org/articles/106075/elife-106075-supp1-v1.xlsx
-
MDAR checklist
- https://cdn.elifesciences.org/articles/106075/elife-106075-mdarchecklist1-v1.docx
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Reporting standard 1
STROBE-MR checklist.
- https://cdn.elifesciences.org/articles/106075/elife-106075-repstand1-v1.docx
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Reassessing the link between adiposity and head and neck cancer: a Mendelian randomization study
eLife 14:RP106075.
https://doi.org/10.7554/eLife.106075.3
