PT - JOURNAL ARTICLE AU - Celia L Gregson AU - Dylan Bergen AU - Paul Leo AU - Richard B. Sessions AU - Lawrie Wheeler AU - April Hartley AU - Scott Youlten AU - Peter I Croucher AU - Aideen M. McInerney-Leo AU - William Fraser AU - Jonathan C.Y. Tang AU - Lisa Anderson AU - Mhairi Marshall AU - Leon Sergot AU - Lavinia Paternoster AU - George Davey-Smith AU - The AOGC Consortium AU - Matthew A Brown AU - Chrissy Hammond AU - John P Kemp AU - Jon H Tobias AU - Emma L Duncan TI - A rare <em>SMAD9</em> mutation identifies the BMP signalling pathway as a potential osteoanabolic target AID - 10.1101/560565 DP - 2019 Jan 01 TA - bioRxiv PG - 560565 4099 - http://biorxiv.org/content/early/2019/02/25/560565.short 4100 - http://biorxiv.org/content/early/2019/02/25/560565.full AB - To identify targets for novel anabolic medicines for osteoporosis, we recruited a large cohort with unexplained high bone mass (HBM). Exome sequencing identified a rare (minor allele frequency 0.0014) missense mutation in SMAD9 (c.65T&gt;C, p.Leu22Pro) segregating with HBM in an autosomal dominant family. The same mutation was identified in another two unrelated individuals with HBM. In-silico protein modelling predicts the mutation severely disrupts the MH1 DNA-binding domain of SMAD9. Affected individuals have bone mineral density [BMD] Z-Scores +3 to +5, with increased volumetric cortical and trabecular BMD, increased cortical thickness, and low/normal bone turnover. Fractures and nerve compressions are not seen. Both genome-wide, and gene-based association testing of heel estimated-BMD in &gt;362,924 UK-Biobank British subjects showed strong associations with SMAD9 (PGWAS=6×10−16; PGENE =8×10−17). Smad9 is highly expressed in murine osteocytes and zebrafish bone tissue. Our findings support SMAD9 as a novel HBM gene, and a potential novel osteoanabolic target.