Genetically proxied vitamin B12 and homocysteine in relation to life course adiposity and body composition

Objective: Observational studies explore the association between vitamin B12 and obesity. However, causality is not reflected by such observations. We performed a bi-directional Mendelian randomization (MR) study to elucidate the causal relationship of vitamin B12 and homocysteine (Hcy) with life course adiposity and body composition.Methods: Two-sample MR analysis was conducted. Independent genetic variants associated with vitamin B12 and Hcy from large-scale genome-wide association studies (GWASs) were utilized as genetic instruments, and their causal effects on five life course adiposity phenotypes (birth weight, body mass index (BMI), childhood BMI, waist circumference, waist-to-hip ratio) and three body compositions (body fat mass, body fat-free mass, body fat percentage) were estimated from UK Biobank, other consortia, and large-scale GWASs. The inverse variance weighting (IVW, main analysis), bi-directional MR, and other six sensitivity MR analyses were performed.Results: Genetically proxied higher vitamin B12 concentrations were robustly associated with reduced BMI (Beta = -0.01, 95% confidence interval (CI) -0.016 to -0.004, P = 7.60E-04), body fat mass (Beta = -0.012, 95%CI -0.018 to -0.007, P = 1.69E-05), and body fat percentage (Beta = -0.005, 95%CI -0.009 to -0.002, P = 4.12E03) per SD unit by IVW and other sensitivity analyses. Stratification analysis showed that these results remained significant in females and at different body sites (all P < 0.05 after Bonferroni correction). Bi-directional analyses showed no reverse causation.Conclusions: This study provides strong evidence for the causal effect of vitamin B12 on adiposity. This gives novel clues for intervening obesity in public health and nutrition.