Identification of known and novel long non-coding RNAs potentially responsible for the effects of BMD GWAS loci

Osteoporosis, characterized by low bone mineral density (BMD), is the most common complex disease affecting bone and constitutes a major societal health problem. Genome-wide association studies (GWASs) have identified over 1100 associations influencing BMD. It has been shown that perturbations to long non-coding RNAs (lncRNAs) influence BMD and the activities of bone cells; however, the extent to which lncRNAs are involved in the genetic regulation of BMD is unknown. Here, we combined the analysis of allelic imbalance (AI) in human acetabular bone fragments with a transcriptome-wide association study (TWAS) and expression quantitative trait loci (eQTL) colocalization analysis using data from the Genotype-Tissue Expression (GTEx) project to identify lncRNAs potentially responsible for GWAS associations. We identified 27 lncRNAs in bone that are located in proximity to a BMD GWAS association and harbor SNPs demonstrating AI. Using GTEx data we identified an additional 31 lncRNAs whose expression was associated (FDR correction<0.05) with BMD through TWAS and had a colocalizing eQTL (regional colocalization probability (RCP)>0.1). The 58 lncRNAs are located in 43 BMD associations. To further support a causal role for the identified lncRNAs, we show that 23 of the 58 lncRNAs are differentially expressed as a function of osteoblast differentiation. Our approach identifies lncRNAs that are potentially responsible for BMD GWAS associations and suggest that lncRNAs play a role in the genetics of osteoporosis.

Systems genetics in diversity outbred mice inform BMD GWAS and identify determinants of bone strength

Genome-wide association studies (GWASs) for osteoporotic traits have identified over 1000 associations; however, their impact has been limited by the difficulties of causal gene identification and a strict focus on bone mineral density (BMD). Here, we use Diversity Outbred (DO) mice to directly address these limitations by performing a systems genetics analysis of 55 complex skeletal phenotypes. We apply a network approach to cortical bone RNA-seq data to discover 66 genes likely to be causal for human BMD GWAS associations, including the genes SERTAD4 and GLT8D2. We also perform GWAS in the DO for a wide-range of bone traits and identify Qsox1 as a gene influencing cortical bone accrual and bone strength. In this work, we advance our understanding of the genetics of osteoporosis and highlight the ability of the mouse to inform human genetics.

Genetics of Osteoporosis

OSTEOPOROSIS is a common disease affecting the majorityof older women and a significant minority ofolder men. It is defined as the gradual reduction in bonestrength with advancing age, particularly in women postmenopause, such that bones fracture with minimal trauma(1– 4). Although fractures of the hip, wrist, and spine areoften focused upon, almost any bone can fracture (5–21). Ageper se is the strongest risk factor for osteoporotic fracture;however, the variance in bone density is similar across allages. A range of hormonal and environmental factorsheighten the risk of osteoporosis, yet together these riskfactors explain only a small proportion of the overall risk.Trauma is an important factor with the event of fracture oftenthe result of a relatively weak bone being subjected to force,such as in a fall. Any bone will fracture if subjected to excessiveforce, e.g., in a motor vehicle accident. Howeverweakened, osteoporotic bones can fracture without any obviousantecedent trauma. This complete spectrum in bonestrength is the focus of this review, particularly the geneticfactors that may influence sensitivity to environmental andhormonal factors. These factors and their interactions contributeto the end result of bone strength in later adult lifewhen the risk for osteoporotic fractures rises.Osteoporosis is one of the major and growing health careproblems around the world largely related to the general

The role of DNA methylation in the disorders of bone metabolism

Osteoporosis is one of multifactorial diseases, it develops from interactions between the genetic component and the environment. However, the universal epigenetic markers of osteoporosis are not yet defined. Finding the risk factors will predict the risk of osteoporosis at the preclinical stage, help define the course and severity of the disease, and develop preventive measures based on them to reduce the risk of fractures. Expanding knowledge in the field of bone biology, especially in the genetics of osteoporosis and osteoimmunology, showed that osteoporosis is a disease that occurs not only due to hormonal or mechanical disorders, but also as a clinically and genetically heterogeneous disease, and there are still unknown pathogenetic links in its structure. Decreases in bone mass and matrix mineralization as well as changes in bone microarchitecture can have different pathogenetic patterns of development and, moreover, there are unknown links of the pathogenesis of osteoporosis. It is possible that DNA methylation is one of these links and a mechanism for epigenetic regulation of gene expression. Evidence exists that this mechanism alongside regulatory miRNAs and post-translational modifications makes a significant contribution to the central processes of bone remodeling; however, the results of various studies vary greatly, and, therefore, there is a need to understand the significance of the accumulated data and to make them consistent. The purpose of this review is to compile and systematize data on the role of DNA methylation in bone metabolism in normal and pathological conditions, in the formation of osteoporosis, and to assess achievements and trends in this field of research and technologies for studying DNA methylation.