Abstract
Although a potential relationship between dietary vitamin B12 (VB12) and heel estimated bone mineral density (eBMD) has been suggested, the detailed phenotypic and genetic associations that underpin this relationship remain unclear. We first assessed the phenotypic association between dietary VB12 and eBMD using linear regression and restricted cubic splines based on data from the UK Biobank (N = 64,326). We then explored the genetic relationship between these traits through a large-scale genome-wide cross-trait analysis, leveraging summary statistics from the hitherto largest genome-wide association studies (Ndietary VB12 = 51,453, NeBMD = 426,824). Observational analysis showed no linear association (β = -0.001, P = 0.63) but an inverted U-shaped relationship (Pnonlinear = 0.045) of dietary VB12 with eBMD. While no overall genetic correlation was found between dietary VB12 and eBMD, two significant local genetic signals were detected at 13q32.3 and 15q26.1. Cross-trait meta-analysis identified seven pleiotropic single-nucleotide polymorphisms (SNPs) shared between dietary VB12 and eBMD, with two showing colocalization (PPH4 > 0.60). Transcriptome-wide association study revealed one shared gene-tissue pair enriched in Brain-Brodmann Area 9. Although no linear causal association was detected, nonlinear Mendelian randomization unveiled a nonlinear relationship between dietary VB12 and eBMD. Both phenotypic and genetic analyses suggest a nonlinear association between dietary VB12 and eBMD. The shared genetic basis underlying these traits highlights common biological mechanisms, providing insights for future mechanistic research on nutritional prevention of osteoporosis.