Sha Linna, Zhang Li, Zhao Xunying, Xiang Rong, Wu Xueyao, Zhu Jiangbo, Hou Jiaojiao, Deng Qin, Qin Chenjiarui, Xiao Changfeng, Qu Yang, Han Tao, Zhou Jinyu, Zheng Sirui, Yu Ting, Song Xin, Yang Bin, Fan Mengyu, Jiang Xia
Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
J Clin Endocrinol Metab. 2025 May 19;110(6):1605-1616. doi: 10.1210/clinem/dgae738.
Despite the well-established regulatory role of vitamin D in maintaining bone health, little is known about the shared genetics and causality of the association between serum 25-hydroxyvitamin D (25OHD) and bone mineral density (BMD).
We aimed to investigate the shared genetic architecture and causal relationship between serum 25OHD and BMD, providing insights into their underlying biological mechanisms.
Leveraging individual-level data from the UK Biobank (UKB) cohort and summary-level data from the genome-wide association studies (GWASs) conducted on European individuals for serum 25OHD (N = 417 580) and estimated heel BMD (eBMD, N = 426 824), we systematically elucidated the shared genetic architecture underlying serum 25OHD and eBMD through a comprehensive genome-wide cross-trait design.
Despite a lack of global genetic correlation (rg=-0.001; P = .95), a statistically significant local signal was discovered at 5p11-5q11.9. Two-sample mendelian randomization (MR) indicated no causal association in the overall population (β=.003, 95% CI, -0.04 to 0.03; P = .93), while positive causal effects were observed in males (β=.005, 95% CI, 0.00 to 0.01; P = .03) and older individuals (β=.009, 95% CI, 0.00∼0.02; P = .01) according to one-sample MR. A total of 49 pleiotropic single-nucleotide variations (SNVs), with 4 novel SNVs (rs1077151, rs79873740, rs12150353, and rs4760401), were identified, and a total of 95 gene-tissue pairs exhibited overlap, predominantly enriched in the nervous, digestive, exocrine/endocrine, and cardiovascular systems. Protein-protein interaction analysis identified RPS9 and RPL7A as hub genes.
This study illuminates the potential health benefits of enhancing serum 25OHD levels to mitigate the risk of osteoporosis among men and individuals older than 65 years. It also unveils a shared genetic basis between serum 25OHD and eBMD, offering valuable insights into the intricate biological pathways.
尽管维生素D在维持骨骼健康方面的调节作用已得到充分证实，但对于血清25-羟基维生素D（25OHD）与骨密度（BMD）之间关联的共同遗传学及因果关系却知之甚少。
我们旨在研究血清25OHD与BMD之间的共同遗传结构及因果关系，以深入了解其潜在的生物学机制。
利用英国生物银行（UKB）队列的个体水平数据以及针对欧洲个体进行的血清25OHD（N = 417580）和估算足跟骨密度（eBMD，N = 426824）的全基因组关联研究（GWAS）的汇总水平数据，我们通过全面的全基因组跨性状设计系统地阐明了血清25OHD和eBMD背后的共同遗传结构。
尽管缺乏整体遗传相关性（rg = -0.001；P = 0.95），但在5p11 - 5q11.9发现了一个具有统计学意义的局部信号。两样本孟德尔随机化（MR）表明在总体人群中无因果关联（β = 0.003，95%CI，-0.04至0.03；P = 0.93），而根据单样本MR，在男性（β = 0.005，95%CI，0.00至0.01；P = 0.03）和老年人（β = 0.009，9%CI，0.00∼0.02；P = 0.01）中观察到正向因果效应。共鉴定出49个多效性单核苷酸变异（SNV），其中包括4个新的SNV（rs1077151、rs79873740、rs12150353和rs4760401），总共95个基因 - 组织对存在重叠，主要富集于神经、消化、外分泌/内分泌和心血管系统。蛋白质 - 蛋白质相互作用分析确定RPS9和RPL7A为中心基因。
本研究阐明了提高血清25OHD水平以降低男性和65岁以上个体患骨质疏松症风险的潜在健康益处。它还揭示了血清25OHD和eBMD之间的共同遗传基础，为复杂的生物学途径提供了有价值的见解。
