Exploring the shared genetic architecture of type 2 diabetes mellitus and bone mineral density.

There is a link between type 2 diabetes mellitus (T2DM) and bone mineral density (BMD), but the genetic reasons behind it are not yet clear. Our study found shared genetic markers and key genes connecting T2DM and BMD. This finding helps us understand their co-occurrence and may lead to new therapeutic strategies.

Purpose: To explore the genetic correlation, causal relationships, and shared risk loci with potential functions between T2DM and BMD.

Methods: Using data from genome-wide association studies (GWAS), we explored the genetic correlation and causality between T2DM and BMD through linkage disequilibrium score regression and bidirectional Mendelian randomization. The phenotype-cell-gene association (PCGA) platform was employed to investigate single-nucleotide polymorphism (SNP) enrichment at the tissue and cell-type levels. Shared risk SNPs were identified through cross-trait meta-analyses and Heritability Estimation from Summary Statistics. We further explored biologically relevant genes using summary-data-based Mendelian randomization (SMR).

Results: Our study revealed a significant positive genetic correlation between T2DM and BMD (r_g = 0.0822, P = 3.84E - 06). The causality between T2DM and BMD was supported by our analyses, showing that T2DM affects BMD (IVW β = 0.035, P = 0.030; GSMR β = 0.107, P = 0.008) and BMD influences T2DM (IVW β = 0.085, P = 0.009; GSMR β = 0.094, P = 0.008). Cross-trait analysis identified 19 shared risk SNPs, including 3 novel pleiotropic SNPs. Tissue-specific SNP heritability enrichment for T2DM and BMD was observed in artery and adipose tissue. Additionally, cell-type-specific SNP heritability enrichment was found in macrophages, endothelial cells, fibroblasts, T cells, and mast cells. SMR identified three shared biologically relevant genes (BTBD16, RNF146, and CENPW) between T2DM and BMD.

Conclusions: These discoveries elucidate the intertwined genetic structures of T2DM and BMD, enhancing our comprehension of the co-occurrence of T2DM and osteoporosis and paving the way for the innovation of targeted therapeutic strategies.