Body mass index and height and risk of cutaneous melanoma: Mendelian randomization analyses

Abstract

Background: Height and body mass index (BMI) have both been positively associated with melanoma risk, although findings for BMI have been less consistent than height. It remains unclear, however, whether these associations reflect causality or are due to residual confounding by environmental and lifestyle risk factors. We re-evaluated these associations using a two-sample Mendelian randomization (MR) approach.

Methods: We identified single nucleotide polymorphisms (SNPs) for BMI and height from separate genome-wide association study (GWAS) meta-analyses. We obtained melanoma SNPs from the most recent melanoma GWAS meta-analysis comprising 12 874 cases and 23 203 controls. We used the inverse variance-weighted estimator to derive separate causal risk estimates across all SNP instruments for BMI and height.

Results: Based on the combined estimate derived from 730 SNPs for BMI, we found no evidence of an association between genetically predicted BMI and melanoma [odds ratio (OR) per one standard deviation (1 SD) (4.6 kg/m2) increase in BMI 1.00, 95% confidence interval (CI): 0.91-1.11]. In contrast, we observed a positive association between genetically-predicted height (derived from a pooled estimate of 3290 SNPs) and melanoma risk [OR 1.08, 95% CI: 1.02-1.13, per 1 SD (9.27 cm) increase in height]. Sensitivity analyses using two alternative MR methods yielded similar results.

Conclusions: These findings provide no evidence for a causal association between higher BMI and melanoma, but support the notion that height is causally associated with melanoma risk. Mechanisms through which height influences melanoma risk remain unclear, and it remains possible that the effect could be mediated through diverse pathways including growth factors and even socioeconomic status.

Keywords: Body mass index; Mendelian randomization; body size; causality; height; melanoma; skin cancer.

Figure 1.

Association of individual single nucleotide polymorphisms with body mass index and melanoma risk. Instrumental variable estimates were derived from 730 body mass index single nucleotide polymorphisms instruments identified in the body mass index genome-wide association study meta-analysis using samples from Genetic Investigation of ANthropometric Traits and the UK Biobank cohort. Error bars represent 95% confidence intervals. The gradients of regression lines colours correspond to the instrumental variable estimates of the effect of body mass index on melanoma risk with different Mendelian randomization (MR) methods compared.

Figure 2.

Association of individual single nucleotide polymorphisms with height and melanoma risk. Instrumental variable estimates were derived from 3290 height single nucleotide polymorphisms instruments identified in the height genome-wide association study meta-analysis using samples from Genetic Investigation of ANthropometric Traits and the UK Biobank cohort. Error bars represent 95% confidence intervals. The gradients of regression lines colours correspond to the instrumental variable estimates of the effect of height on melanoma risk with different Mendelian randomization (MR) methods compared.