Integrative Genomic Evidence for a Putative Causal Association Between Latent Epigenetic Ageing and Bone Mineral...

To investigate whether latent epigenetic ageing is causally associated with bone mineral density using Mendelian randomization and to identify monocyte-specific genes potentially mediating this relationship. A latent epigenetic ageing factor was constructed from four DNA methylation clocks (GrimAge, Hannum, PhenoAge, and intrinsic epigenetic age acceleration) using Genomic structural equation modelling. Causal effects on heel estimated bone mineral density (eBMD; N = 426,824) were tested by two-sample Mendelian randomization (MR) and the pleiotropy-robust CAUSE framework. Monocyte-specific mediating genes were identified through single-cell PrediXcan with OneK1K prediction models, Bayesian colocalization, SMR-HEIDI, and causal transcriptome-wide association study fine-mapping. Functional consequences of prioritized variants were characterized using AlphaGenome, and key candidates were examined at the protein level in RANKL-induced THP-1 osteoclast differentiation as a first step toward validation in primary human monocyte-derived osteoclasts. Forward MR provided evidence consistent with a potential causal association between the latent ageing factor and eBMD (inverse-variance weighted β = 0.067, P = 3.6 × 10^-4), with concordant sensitivity and CAUSE estimates; reverse MR was null. Single-cell PrediXcan revealed monocyte enrichment and an 11-gene pleiotropic core set. Colocalization and SMR-HEIDI converged on IFT80 (posterior probability of hypothesis 4 = 0.769) and TRIM59 (posterior probability of hypothesis 4 = 0.886) at chromosome 3. Causal transcriptome-wide association study fine-mapping nominated 45 high-confidence eBMD genes, independently confirming both IFT80 (PIP = 0.981) and TRIM59 (PIP = 0.936) among the top-ranked candidates. AlphaGenome highlighted regulatory perturbations at two chr3 variants. Western blot confirmed significant IFT80 downregulation and TRIM59 upregulation during osteoclast differentiation, consistent with computational predictions. Multi-layered genomic evidence provides convergent support for a putative causal association between latent epigenetic ageing and bone mineral density through monocyte-specific regulatory mechanisms, identifying the TRIM59-IFT80 locus and 45 candidate genes as priority targets for mechanistic validation.