Paget’s disease of bone (PDB) is a common disease characterised by focal areas of increased bone turnover leading to symptoms of bone pain, deformity, osteoarthritis and other complications. Genetic factors play an important role in PDB and mutations in SQSTM1 gene are responsible for ~10% of PDB cases with high penetrance. We have recently identified seven additional susceptibility loci for PDB using genome-wide association studies (Albagha et al, 2011; Nat Genet). These recently identified loci have a combined effect that explained about 13% of familial risk suggesting that other genetic factors remain to be identified. The aims of this project are three fold: 1) to define the functional variants in the recently identified susceptibility loci using targeted DNA sequencing, 2) To identify novel genetic variants for disease susceptibility using exome sequencing in PDB patients without SQSTM1 mutations, 3) To investigate the role of epigenetic factors and their interaction with genetic factors in the pathogenesis of PDB. We will study genome-wide DNA methylation patterns in PDB patients and controls to identify differentially methylated sites associated with PDB. The contribution of epigenetic factors to the focal nature of PDB will be studied using an animal model of PDB to assess if epigenetic changes are specific to bone lesions and to determine if these changes contribute to disease development or occur as a consequence of the disease. Identification of genetic and epigenetic factors that predispose to PDB will increase our understanding of disease mechanisms and could also identify novel molecular pathways that could form targets for new therapeutic treatment not only for Paget’s disease, but also other diseases associated with increased bone turnover. These factors could be used as markers for disease susceptibility to assess people at risk of developing PDB later in life and target those with the highest risk for early treatment.