Reassessing the causal role of obesity in breast cancer susceptibility: a comprehensive multivariable Mendelian randomization investigating the distribution and timing of exposure

Abstract

Background: Previous Mendelian randomization (MR) studies on obesity and risk of breast cancer adopted a small number of instrumental variables and focused mainly on the crude total effect. We aim to investigate the independent causal effect of obesity on breast cancer susceptibility, considering the distribution of fat, covering both early and late life.

Methods: Using an enlarged set of female-specific genetic variants associated with adult general [body mass index (BMI)] and abdominal obesity [waist-to-hip ratio (WHR) with and without adjustment for BMI, WHR and WHRadjBMI] as well as using sex-combined genetic variants of childhood obesity (childhood BMI), we performed a two-sample univariable MR to re-evaluate the total effect of each obesity-related exposure on overall breast cancer (Ncase = 133 384, Ncontrol = 113 789). We further looked into its oestrogen receptor (ER)-defined subtypes (NER+ = 69 501, NER- = 21 468, Ncontrol = 105 974). Multivariable MR was applied to estimate the independent causal effect of each obesity-related exposure on breast cancer taking into account confounders as well as to investigate the independent effect of adult and childhood obesity considering their inter-correlation.

Results: In univariable MR, the protective effects of both adult BMI [odds ratio (OR) = 0.89, 95% CI = 0.83-0.96, P = 2.06 × 10-3] and childhood BMI (OR = 0.78, 95% CI = 0.70-0.87, P = 4.58 × 10-6) were observed for breast cancer overall. Comparable effects were found in ER+ and ER- subtypes. Similarly, genetically predicted adult WHR was also associated with a decreased risk of breast cancer overall (OR = 0.87, 95% CI = 0.80-0.96, P = 3.77 × 10-3), restricting to ER+ subtype (OR = 0.88, 95% CI = 0.80-0.98, P = 1.84 × 10-2). Conditional on childhood BMI, the effect of adult general obesity on breast cancer overall attenuated to null (BMI: OR = 1.00, 95% CI = 0.90-1.10, P = 0.96), whereas the effect of adult abdominal obesity attenuated to some extent (WHR: OR = 0.90, 95% CI = 0.82-0.98, P = 1.49 × 10-2; WHRadjBMI: OR = 0.92, 95% CI = 0.86-0.99, P = 1.98 × 10-2). On the contrary, an independent protective effect of childhood BMI was observed in breast cancer overall, irrespective of adult measures (adjusted for adult BMI: OR = 0.84, 95% CI = 0.77-0.93, P = 3.93 × 10-4; adjusted for adult WHR: OR = 0.84, 95% CI = 0.76-0.91, P = 6.57 × 10-5; adjusted for adult WHRadjBMI: OR = 0.80, 95% CI = 0.74-0.87, P = 1.24 × 10-7).

Conclusion: Although successfully replicating the inverse causal relationship between adult obesity-related exposures and risk of breast cancer, our study demonstrated such effects to be largely (adult BMI) or partly (adult WHR or WHRadjBMI) attributed to childhood obesity. Our findings highlighted an independent role of childhood obesity in affecting the risk of breast cancer as well as the importance of taking into account the complex interplay underlying correlated exposures.

Keywords: Childhood adiposity; Mendelian randomization; abdominal obesity; breast cancer; general obesity.

Figure 1

Analytical schematic diagram of the Mendelian randomization (MR) analysis implemented in this study (a) Univariable MR analysis; (b) multivariable MR analysis, including two models: (i) confounder model; (ii) pleiotropic model. G represents genetic variants (single-nucleotide polymorphisms, SNPs) that reliably predict the exposure variable (X) and are used as instrumental variables to represent exposure. G₁ and G₂ represent SNPs that specifically affect X₁ and X₂, respectively, whereas G₁₂ represents SNPs that affect both X₁ and X₂ simultaneously. Thick lines illustrate the causal effect confirmed by the current analysis. BMI, body mass index; WHR, waist-to-hip ratio; WHR_adjBMI, waist-to-hip ratio adjusted for body mass index; ER, oestrogen receptor.

Figure 2

Estimated total effects of obesity-related traits on the risk of breast cancer using univariable Mendelian randomization Boxes denote the point estimates of causal effects, and error bars denote 95% confidence intervals. Asterisks (*) denote the tests survived false discovery rate (FDR) correction (P_FDR < 0.05). Inverse-variance weighted approach was used as primary analysis; MR–Egger, weighted-median and MR-PRESSO were used as sensitivity analyses. BMI, body mass index; WHR, waist-to-hip ratio; WHR_adjBMI, waist-to-hip ratio adjusted for body mass index; ER, oestrogen receptor; No. SNP, number of instrumental variables; OR, odds ratio.

Figure 3

Independent effects of genetically predicted obesity-related traits on the risk of breast cancer after adjusting for each confounder separately and together using multivariable Mendelian randomization The y-axis details the genetically predicted confounder(s) for which adjustment was made and the x-axis details the odds ratios and 95% confidence intervals per 1-standard deviation increase in exposure. Asterisks (*) denote the tests survived false discovery rate (FDR) correction (P_FDR < 0.05). Total effect refers to the estimate derived from univariable Mendelian randomization. BMI, body mass index; WHR, waist-to-hip ratio; WHR_adjBMI, waist-to-hip ratio adjusted for body mass index; ER, oestrogen receptor; AAM, age at menarche; ANM, age at natural menopause; OR, odds ratio.