Body Shape Phenotypes And Breast Cancer Risk: A Mendelian Randomization Analysis.

Background: Observational and genetic studies have linked different anthropometric traits to breast cancer risk, with inconsistent results. We aimed to investigate the association between body shape defined by principal component (PC) analysis of anthropometric traits (body mass index (BMI), height, weight, waist-to-hip ratio (WHR), waist and hip circumference) and overall breast cancer risk and by sub-type (luminal A, luminal B, HER2+, triple negative and luminal B/HER2 negative). Methods: : We performed two-sample Mendelian randomization analyses to assess the association between 188 genetic variants robustly linked to the first three PCs and breast cancer (133,384 combined pre- and post-menopausal cases/113,789 controls from the Breast Cancer Association Consortium (BCAC)). Results: : PC1 (general adiposity) was inversely associated with overall breast cancer risk (odds ratio (OR) 0.89 [95% confidence interval (CI) 0.81-0.98]; p-value = 0.016). PC2 (tall with low WHR) was weakly positively associated with overall breast cancer risk (OR = 1.05 [95% CI: 0.98-1.12]; p-value = 0.135), but with a confidence interval including the null. PC3 (tall with large WHR) was not associated with overall breast cancer risk. Some of these associations differed by breast cancer sub-types. For instance, PC2 was positively associated with risk of luminal A breast cancer sub-type (OR = 1.09 [95% CI: 1.01-1.18]; p-value = 0.02). Conclusions: : Our study provides evidence for potential causal associations between body shape and breast cancer risk and breast cancer sub-types highlighting the importance to also assess body morphology holistically.