Boudin Eveline, Fijalkowski Igor, Hendrickx Gretl, Van Hul Wim
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Mol Cell Endocrinol. 2016 Sep 5;432:3-13. doi: 10.1016/j.mce.2015.12.021. Epub 2015 Dec 30.
Bone mineral density (BMD) is a quantitative traits used as a surrogate phenotype for the diagnosis of osteoporosis, a common metabolic disorder characterized by increased fracture risk as a result of a decreased bone mass and deterioration of the microarchitecture of the bone. Normal variation in BMD is determined by both environmental and genetic factors. According to heritability studies, 50-85% of the variance in BMD is controlled by genetic factors which are mostly polygenic. In contrast to the complex etiology of osteoporosis, there are disorders with deviating BMD values caused by one mutation with a large impact. These mutations can result in monogenic bone disorders with either an extreme high (sclerosteosis, Van Buchem disease, osteopetrosis, high bone mass phenotype) or low BMD (osteogenesis imperfecta, juvenile osteoporosis, primary osteoporosis). Identification of the disease causing genes, increased the knowledge on the regulation of BMD and highlighted important signaling pathways and novel therapeutic targets such as sclerostin, RANKL and cathepsin K. Genetic variation in genes involved in these pathways are often also involved in the regulation of normal variation in BMD and osteoporosis susceptibility. In the last decades, identification of genetic factors regulating BMD has proven to be a challenge. Several approaches have been tested such as linkage studies and candidate and genome wide association studies. Although, throughout the years, technological developments made it possible to study increasing numbers of genetic variants in populations with increasing sample sizes at the same time, only a small fraction of the genetic impact can yet be explained. In order to elucidate the missing heritability, the focus shifted to studying the role of rare variants, copy number variations and epigenetic influences. This review summarizes the genetic cause of different monogenic bone disorders with deviating BMD and the knowledge on genetic factors explaining normal variation in BMD and osteoporosis risk.
骨密度（BMD）是一种定量性状，用作骨质疏松症诊断的替代表型。骨质疏松症是一种常见的代谢性疾病，其特征是由于骨量减少和骨微结构退化导致骨折风险增加。BMD的正常变异由环境和遗传因素共同决定。根据遗传力研究，BMD变异的50 - 85%由遗传因素控制，这些因素大多是多基因的。与骨质疏松症复杂的病因不同，存在一些由单个具有重大影响的突变导致BMD值异常的疾病。这些突变可导致单基因骨病，其BMD要么极高（骨硬化症、范布赫姆病、石骨症、高骨量表型）要么极低（成骨不全、青少年骨质疏松症、原发性骨质疏松症）。致病基因的鉴定增加了对BMD调节的认识，并突出了重要的信号通路和新的治疗靶点，如硬化蛋白、核因子κB受体活化因子配体（RANKL）和组织蛋白酶K。参与这些通路的基因中的遗传变异通常也参与BMD正常变异和骨质疏松症易感性的调节。在过去几十年中，鉴定调节BMD的遗传因素已被证明是一项挑战。已经测试了几种方法，如连锁研究、候选基因研究和全基因组关联研究。尽管多年来技术发展使得能够在样本量不断增加的人群中同时研究越来越多的遗传变异，但仍只能解释一小部分遗传影响。为了阐明缺失的遗传力，研究重点转向研究罕见变异、拷贝数变异和表观遗传影响的作用。本综述总结了不同BMD异常的单基因骨病的遗传病因，以及关于解释BMD正常变异和骨质疏松症风险的遗传因素的知识。
