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Bone mineral density (BMD) is a measure of osteoporosis and is useful in evaluating the risk of fracture. In a genome-wide association study of BMD among 20,100 Icelanders, with follow-up in 10,091 subjects of European and East-Asian descent, we found a new BMD locus that harbours the  PTCH1  gene, represented by rs28377268 (freq. 11.4–22.6%) that associates with reduced spine BMD ( P =1.0 × 10 −11 ,  β =−0.09). We also identified a new spine BMD signal in  RSPO3 , rs577721086 (freq. 6.8%), that associates with increased spine BMD ( P =6.6 × 10 −10 ,  β =0.14). Importantly, both variants associate with osteoporotic fractures and affect expression of the  PTCH1  and  RSPO3  genes that is in line with their influence on BMD and known biological function of these genes. Additional new BMD signals were also found at the  AXIN1  and  SOST  loci and a new lead SNP at the  EN1  locus.

Sequence variants in the PTCH1 gene associate with spine bone mineral density and osteoporotic fractures