Osteoporosis is the most prevalent metabolic bone disease in the world.  It is a highly heritable condition, but until recently most of the contributing genes were unknown.  

In the last several years, genome-wide approaches (GWAS) have transformed our understanding of many heritable diseases, including osteoporosis, with GWAS identifying over 56 genes determining bone mineral density (BMD) and fracture.   The Australian Osteoporosis Genetics Consortium contributed significantly to this effort, with our unique GWAS approach using an extreme truncated proband discovery cohort with a replication cohort drawn from the normal population.  Not only did we confirm 21 of the then 26 known genes, we identified a further 6 new genes.  Further, we demonstrated that for quantitative traits, such as BMD, an extreme truncate discovery cohort is an extremely efficient study design.

However, there are limitations to GWAS and the exact disease-causing mutation is usually not identified through GWAS but requires further mapping.  Whilst this can include traditional fine-mapping approaches, a new paradigm in disease-gene identification is next-generation sequencing (NGS).

This approach allows the sequencing of either the whole or part (e.g. the exome) of the genome to be sequenced in a single experiment, with comparison of the individual’s sequence back to the reference genome.  We have recently used NGS in families and individuals with unmapped skeletal dysplasias, mapping novel genes even with only a few affected individuals.   These studies in patients with skeletal dysplasia are of great relevance to the general population also, as they shed light on normal bone development and control.   Further, NGS can be applied to population extreme cohorts, such as the AOGC, both to fine-map already identified loci and to find new genes contributing to osteoporosis and fracture.