Comprehensive Analysis of the Genetic and Epigenetic Mechanisms of Osteoporosis and Bone Mineral Density

Abstract

Osteoporosis is a skeletal disorder characterized by a systemic impairment of bone mineral density (BMD). Genome-wide association studies (GWAS) have identified hundreds of susceptibility loci for osteoporosis and BMD. However, the vast majority of susceptibility loci are located in non-coding regions of the genome and provide limited information about the genetic mechanisms of osteoporosis. Herein we performed a comprehensive functional analysis to investigate the genetic and epigenetic mechanisms of osteoporosis and BMD. BMD and osteoporosis are found to share many common susceptibility loci, and the corresponding susceptibility genes are significantly enriched in bone-related biological pathways. The regulatory element enrichment analysis indicated that BMD and osteoporosis susceptibility loci are significantly enriched in 5 UTR and DNase I hypersensitive sites (DHSs) of peripheral blood immune cells. By integrating GWAS and expression Quantitative Trait Locus (eQTL) data, we found that 15 protein-coding genes are regulated by the osteoporosis and BMD susceptibility loci. Our analysis provides new clues for a better understanding of the pathogenic mechanisms and offers potential therapeutic targets for osteoporosis.

Helicobacter pylori Related Diseases and Osteoporotic Fractures (Narrative Review)

“…Notes: Recent genetic studies have challenged some long-assumed risk factors for OP/OF. Mendelian randomization analyses identified BMD [ 413 , 635 , 636 , 637 ], serum estradiol concentrations (in men) [ 638 ] and cigarette smoking [ 639 ] as causal risk factors for OP/OFs, whereas genetic predisposition to lower levels of vitamin D and milk calcium intake [ 635 , 636 , 639 , 640 ], serum testosterone [ 638 ] and inflammation markers [ 641 , 642 ], as well as early menopause; late puberty, chronic (including CVD, DM and IBD) [ 413 , 414 , 643 ] and neuropsychiatric diseases (Alzheimer’s disease, schizophrenia and bipolar disorder) [ 644 ], alcohol consumption [ 645 ] and alcohol dependence [ 639 ] did not show causal effects on BMD and fracture risk. The genetic studies overcome many limitations of the previous observational studies but also contain potential bias; “the Mendelian randomization study design cannot be used to assess whether complications or treatment of those diseases influence fracture risk” [ 636 ].…”

Multitrait GWAS to connect disease variants and biological mechanisms

“…We analyzed the 36 GWASs of European ancestry ( S1 – S3 Tables ) using the aforementioned multitrait approaches applied to seven phenotype sets: five medical-based sets ( Immunity , Anthropometry , Metabolism , Cardiovascular and Psychiatric ), a BMI related set including anthropometry traits and lipids (referred further as the Composite set), and finally all 36 phenotypes jointly ( Fig 2 ). Note that we included bone mineral density traits in the Immunity set because an enrichment of BMD genome wide significant loci in immune pathways and immune cell regulatory regions has been previously reported[ 34 , 35 ]. We derived the overlap of significant loci of the multitrait tests per phenotype set ( S15 – S21 Figs ), and after merging all analyses ( Fig 3A ).…”

Screening of Phytochemicals against Osteoporosis: Molecular Docking and Simulation-Based Computational Approaches

“…Most people ignore the back pain and treated them as just a symbol of getting older and do not undergo the diagnosis and proper treatment. This disease often remains undiagnosed until the fractures appear so the only focus given to its medication therapies was to reduce the incidences of further fractures [3]. This disease is most common in menopause women but elderly men may also be affected by it.…”