The discovery that sclerostin is the defective protein underlying the rare heritable bone mass disorder, sclerosteosis, ultimately led to development of anti-sclerostin antibodies as a new treatment for osteoporosis. In the era of large scale GWAS, many additional genetic signals associated with bone mass and related traits have since been reported. However, how best to interrogate these signals in order to identify the underlying gene responsible for these genetic associations, a prerequisite for identifying drug targets for further treatments, remains a challenge. The resources available for supporting functional genomics research continues to expand, exemplified by "multi-omics" database resources, with improved availability of datasets derived from bone tissues. These databases provide information about potential molecular mediators such as mRNA expression, protein expression, and DNA methylation levels, which can be interrogated to map genetic signals to specific genes based on identification of causal pathways between the genetic signal and the phenotype being studied. Functional evaluation of potential causative genes has been facilitated by characterization of the "osteocyte signature", by broad phenotyping of knockout mice with deletions of over 7,000 genes, in which more detailed skeletal phenotyping is currently being undertaken, and by development of zebrafish as a highly efficient additional in vivo model for functional studies of the skeleton. Looking to the future, this expanding repertoire of tools offers the hope of accurately defining the major genetic signals which contribute to osteoporosis. This may in turn lead to the identification of additional therapeutic targets, and ultimately new treatments for osteoporosis.
Bibliographical noteFunding Information:
This workshop was organized by the Royal Osteoporosis Society (ROS) Osteoporosis and Bone Research Academy Causes Working Group, funded by the Royal Osteoporosis Society. We are grateful to Dr Belinda Thompson and Mrs Francesca Thompson for their assistance in organizing the workshop. The ROS Osteoporosis and Bone Research Academy Causes Working Group membership comprises: Prof Stuart Ralston (Chair), Prof Jon Tobias, Dr Owen Cronin, Prof Emma Duncan, Dr Celia Gregson, Dr Nuria Gunabens, Dr Fadil Hannan, Dr Rosemary Hollick, Dr Richard Keen, Prof Susan Lanham-New, Prof Tim Spector, Mrs Mary Bishop, Mrs Joy Capel, Mr Nic Vine, Mrs Karen Whitehead MBE. We acknowledge collaboration with the GEMSTONE COST ACTION (CA18139).
© Copyright © 2021 Tobias, Duncan, Kague, Hammond, Gregson, Bassett, Williams, Min, Gaunt, Karasik, Ohlsson, Rivadeneira, Edwards, Hannan, Kemp, Gilbert, Alonso, Hassan, Compston and Ralston.
- genome-wide association study
- bone mineral density
- mouse model
- “omics” data