Genetics of Paget's Disease of Bone

Genetic factors play an important role in the pathogenesis of Paget's disease of bone (PDB). Familial clustering is common and first degree relatives of patients with the disease carry a seven-fold increased risk of developing the disease as compared with the general population. Linkage analysis in families coupled with genome-wide association studies have identified several loci and candidate gene that predispose to Paget's disease over recent years. The most important gene for familial Paget's is SQSTM1 which encodes p62 a protein involved in signal transduction downstream of the RANK receptor. Other candidate genes include CSF1, TNFRSF11A, TM7SF4, OPTN, and RIN3. Most of these genes are known to play a role in osteoclast differentiation and function which suggests that the abnormal osteoclast function in Paget's may be due to dysregulation of expression or function of these genes. Additional loci have been identified that predispose to PDB where the causal gene remains to be determined. Further research into the genetic basis of Paget's is likely to identify genetic variants that would be clinically useful in predicting disease occurrence and targeting treatment.