The role of size, shape and structure of bones and joints, in explaining common musculoskeletal diseases (360G-Wellcome-209233_Z_17_Z)

Combining our expertise in epidemiological, genetic and causal pathway analysis, with that in statistical shape modelling (SSM), our collaboration aims to develop new approaches for the prediction, prevention and treatment of common musculoskeletal diseases, by improving understanding of the role of size, shape and structure of bones and joints in their pathogenesis. For example, we aim to establish the roles of hip and knee shape in prevalent and incident osteoarthritis (OA), and fat mass and muscle strength in vertebral fractures and scoliosis, as well as pursuing hypothesis-free approaches. Seven endophenotypes will be generated from the unique dual energy X-ray absorptiometry (DXA) resource of the UKBiobank Imaging Enhancement Study; following automation of existing algorithms, scans from 100,000 individuals to be examined (work package (WP)1). Cross sectional and longitudinal relationships between these endophenotypes and hypothesized risk factors and disease outcomes will subsequently be analysed, providing a basis for new disease prediction algorithms (WP2). Genome wide association studies (GWAS; WP3) and functional annotation (WP4) will identify novel genetic mechanisms and putative drug targets. Mendelian Randomisation studies (WP5), exploiting GWAS results from WP3, will establish whether relationships identified in WP2 reflect causal associations, suggesting new approaches for disease prevention through risk factor modification.