Genetics of osteoporosis: searching for candidate genes for bone fragility

Abstract

The pathogenesis of osteoporosis, a common disease with great morbidity and mortality, comprises environmental and genetic factors. As with other complex disorders, the genetic basis of osteoporosis has been difficult to identify. Nevertheless, several approaches have been undertaken in the past decades in order to identify candidate genes for bone fragility, including the study of rare monogenic syndromes with striking bone phenotypes (e.g. osteogenesis imperfecta and osteopetroses), the analysis of individuals or families with extreme osteoporotic phenotypes (e.g. idiopathic juvenile and pregnancy-related osteoporosis), and, chiefly, genome-wide association studies (GWAS) in large populations. Altogether, these efforts have greatly increased the understanding of molecular mechanisms behind bone remodelling, which has rapidly translated into the development of novel therapeutic strategies, exemplified by the tales of cathepsin K (CTSK) and sclerostin (SOST). Additional biological evidence of involvement in bone physiology still lacks for several candidate genes arisen from GWAS, opening an opportunity for the discovery of new mechanisms regulating bone strength, particularly with the advent of high-throughput genomic technologies. In this review, candidate genes for bone fragility will be presented in comprehensive tables and discussed with regard to how their association with osteoporosis emerged, highlighting key players such as LRP5, WNT1 and PLS3. Current limitations in our understanding of the genetic contribution to osteoporosis, such as yet unidentified genetic modifiers, may be overcome in the near future with better genotypic and phenotypic characterisation of large populations and the detailed study of candidate genes in informative individuals with marked phenotype. Arch Endocrinol Metab. 2016;60(4):391-401

Identification of a core module for bone mineral density through the integration of a co-expression network and GWAS data

“…The purple module was the most significantly enriched (OR=5.4, P adj = 1.6 × 10 −34 ). We also compiled a list of 35 known drivers of monogenic bone diseases associated with osteoblast dysfunction, including osteogenesis imperfecta, hyperostosis, and osteosclerosis ( Supplemental File 8 ) 30–34 . Again, the purple module, containing 11 of 35 (31.4%) monogenic disease genes, was the most significantly enriched (OR = 21.3, Padj = 6.9 × 10 −9 ) ( Figure 2E ).…”

“…We also curated a list of genes associated with monogenic bone disorders using a literature review, specifically focusing on genes that disrupt osteoblast function, leading to monogenic bone disorders 30–34 ( Supplemental File 8 ). We used a fisher’s exact test to measure the statistical significance of the representation of genes with associated mouse knockout bone phenotypes and monogenic bone disease in each module.…”

MECHANISMS IN ENDOCRINOLOGY: Genetics of human bone formation

“…Throughout the years, these studies lead to the identification of a large number associated (common) variants in over 90 genes or 70 loci. For approximately half of the associated genes additional evidence that for their involvement in the regulation of bone development or metabolism is available (102). Identification of the role of the other genes in the regulation of bone metabolism will contribute to the identification of novel functional pathways.…”

A role for theMEGF6gene in predisposition to osteoporosis

“…Osteoporosis is a common skeletal disorder characterized by deterioration of bone mineral density (BMD) and increased risk of fracture (1). Identification of genetic factors that have a strong influence on disease could enhance screening and knowledge concerning biological pathways involved.…”