Unveiling the mysteries of the genetics of osteoporosis

Introduction Osteoporosis is a common disease characterised by low bone mineral density and an increased risk of fragility fractures. We conducted a literature review of relevant studies relating to the genetics of osteoporosis. Family studies have revealed that bone density and fractures have a strong heritable component but environmental factors also play an important role. This makes identification of the causative genetic variants challenging. Linkage analysis has been successful in identifying the genes responsible for rare inherited diseases associated with abnormalities of bone mass but has been of limited value in osteoporosis. In contrast, genome-wide association studies in large cohort studies have identified 56 loci with robust evidence of association with bone density and 14 loci that predispose to fractures. Although the effect size of the implicated variants is small, many of the loci contain genes known to be involved in regulating bone cell activity through the RANK and Wnt signalling pathways, whereas others contain novel genes not previously implicated in bone metabolism. In a few instances, whole genome and exome sequencing have been successfully used to identify rare variants of large effect size that influence susceptibility to osteoporosis. A future challenge will be to conduct fine mapping and functional analysis of the loci implicated in osteoporosis in order to identify the causal genetic variants and examine the mechanisms by which they influence bone cell function and bone mass. Ultimately this may lead to the identification of biomarkers for susceptibility to osteoporosis and fractures or new therapeutic targets.