Feng Xinran, Xu Hongbin, Guo Qian, Wang Zeying, Ba Ruikai, Xuan Kun, Ban Jinghao
Second Medical Center, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China.
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China.
Arch Osteoporos. 2025 Jun 23;20(1):80. doi: 10.1007/s11657-025-01568-7.
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.
To explore the genetic correlation, causal relationships, and shared risk loci with potential functions between T2DM and BMD.
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).
Our study revealed a significant positive genetic correlation between T2DM and BMD (r = 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.
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.
2型糖尿病（T2DM）与骨矿物质密度（BMD）之间存在联系，但其背后的遗传原因尚不清楚。我们的研究发现了连接T2DM和BMD的共享遗传标记和关键基因。这一发现有助于我们理解它们的共同出现，并可能带来新的治疗策略。
探讨T2DM与BMD之间的遗传相关性、因果关系以及具有潜在功能的共享风险位点。
利用全基因组关联研究（GWAS）的数据，我们通过连锁不平衡评分回归和双向孟德尔随机化来探讨T2DM与BMD之间的遗传相关性和因果关系。采用表型-细胞-基因关联（PCGA）平台在组织和细胞类型水平上研究单核苷酸多态性（SNP）富集情况。通过跨性状荟萃分析和汇总统计的遗传力估计来识别共享风险SNP。我们使用基于汇总数据的孟德尔随机化（SMR）进一步探索生物学相关基因。
我们的研究揭示了T2DM与BMD之间存在显著的正遗传相关性（r = 0.0822，P = 3.84E - 06）。我们的分析支持了T2DM与BMD之间的因果关系，表明T2DM影响BMD（逆方差加权β = 0.035，P = 0.030；广义汇总孟德尔随机化β = 0.107，P = 0.008），且BMD影响T2DM（逆方差加权β = 0.085，P = 0.009；广义汇总孟德尔随机化β = 0.094，P = 0.008）。跨性状分析确定了19个共享风险SNP，包括3个新的多效性SNP。在动脉和脂肪组织中观察到T2DM和BMD的组织特异性SNP遗传力富集。此外，在巨噬细胞、内皮细胞、成纤维细胞、T细胞和肥大细胞中发现了细胞类型特异性SNP遗传力富集。SMR确定了T2DM和BMD之间的三个共享生物学相关基因（BTBD16、RNF146和CENPW）。
这些发现阐明了T2DM和BMD相互交织的遗传结构，增强了我们对T2DM和骨质疏松症共同发生的理解，并为靶向治疗策略的创新铺平了道路。
