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

IF 2.8 3区医学 Q2 ENDOCRINOLOGY & METABOLISM

Archives of Osteoporosis Pub Date : 2025-06-23 DOI:10.1007/s11657-025-01568-7

Xinran Feng, Hongbin Xu, Qian Guo, Zeying Wang, Ruikai Ba, Kun Xuan, Jinghao Ban

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引用次数: 0

Abstract

Summary

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.

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探讨2型糖尿病与骨密度的共同遗传结构。

2型糖尿病（T2DM）与骨密度（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T2DM和BMD之间的共同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发生，并可能导致新的治疗策略。目的：探讨T2DM和BMD之间的遗传相关性、因果关系以及共同的危险位点与潜在功能。方法：利用全基因组关联研究（GWAS）的数据，通过连锁不平衡评分回归和双向孟德尔随机化，探讨T2DM和BMD之间的遗传相关性和因果关系。利用表型-细胞-基因关联（PCGA）平台在组织和细胞水平上研究单核苷酸多态性（SNP）的富集。通过跨性状荟萃分析和汇总统计的遗传力估计来确定共有风险snp。我们使用基于汇总数据的孟德尔随机化（SMR）进一步探索了生物学相关基因。结果：T2DM与BMD呈显著正相关（rg = 0.0822, P = 3.84E - 06）。我们的分析支持T2DM与BMD之间的因果关系，显示T2DM影响BMD (IVW β = 0.035, P = 0.030；GSMR β = 0.107, P = 0.008)和BMD影响T2DM (IVW β = 0.085, P = 0.009；β = 0.094, p = 0.008)。跨性状分析鉴定出19个共有风险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发现T2DM和BMD之间有三个共享的生物学相关基因（BTBD16、RNF146和CENPW）。结论：这些发现阐明了T2DM和BMD的相互交织的遗传结构，增强了我们对T2DM和骨质疏松症共发的理解，并为创新靶向治疗策略铺平了道路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Archives of Osteoporosis ENDOCRINOLOGY & METABOLISMORTHOPEDICS -ORTHOPEDICS

CiteScore

5.50

自引率

10.00%

发文量

133

期刊介绍： Archives of Osteoporosis is an international multidisciplinary journal which is a joint initiative of the International Osteoporosis Foundation and the National Osteoporosis Foundation of the USA. The journal will highlight the specificities of different regions around the world concerning epidemiology, reference values for bone density and bone metabolism, as well as clinical aspects of osteoporosis and other bone diseases.