The genetics of bone mass and susceptibility to bone diseases

Abstract

Osteoporosis is characterized by low bone mass and an increased risk of fracture. Genetic factors, environmental factors and gene-environment interactions all contribute to a person's lifetime risk of developing an osteoporotic fracture. This Review summarizes key advances in understanding of the genetics of bone traits and their role in osteoporosis. Candidate-gene approaches dominated this field 20 years ago, but clinical and preclinical genetic studies published in the past 5 years generally utilize more-sophisticated and better-powered genome-wide association studies (GWAS). High-throughput DNA sequencing, large genomic databases and improved methods of data analysis have greatly accelerated the gene-discovery process. Linkage analyses of single-gene traits that segregate in families with extreme phenotypes have led to the elucidation of critical pathways controlling bone mass. For example, components of the Wnt-β-catenin signalling pathway have been validated (in both GWAS and functional studies) as contributing to various bone phenotypes. These notable advances in gene discovery suggest that the next decade will witness cataloguing of the hundreds of genes that influence bone mass and osteoporosis, which in turn will provide a roadmap for the development of new drugs that target diseases of low bone mass, including osteoporosis.

Osteoporosis: The Result of an ‘Aged’ Bone Microenvironment

“…As early as 2002, mutations involving several canonical WNT pathway components featuring LRP5 and SOST have been reported to result in high bone mass, generating tremendous interest in targeting WNT signaling to treat osteoporosis. Recent waves of genome-wide association studies (GWAS) of age-related osteoporosis have corroborated the validity of this approach, since LRP5, DKK1, SOST and other genes encoding components of the WNT pathway have emerged as contributing factors to bone mass variations[12]. Furthermore, several inhibitors of WNT antagonists including DKK1, WIF-1 and SOST have been suggested as putative candidates [1].…”

A systems approach to renal inflammation in SLE

“…Genome wide association studies (GWAS) have been extremely successful in identifying susceptibility loci for many disease phenotypes, including SLE and related endophenotypes (68, 69) and have led to successful therapeutic approaches in other diseases (70, 71). Single nucleotide polymorphisms (SNPs) that are linked to disease phenotype may be found within as well as outside coding regions and can impact the disease trait via associated transcript expression changes.…”

Epigenetics and Bone Remodeling

“…Several large genome-wide association studies have been undertaken to examine genetic contributions to low bone mineral density (BMD) [11]. Although many genes have been associated with BMD (estimates are around 500), the strength of these associations are all relatively low.…”