An Atlas of Human and Murine Genetic Influences on Osteoporosis

Osteoporosis is a common debilitating chronic disease diagnosed primarily using bone mineral density (BMD). We undertook a comprehensive assessment of human genetic determinants of bone density in 426,824 individuals, identifying a total of 518 genome-wide significant loci, (301 novel), explaining 20% of the total variance in BMD, as estimated by heel quantitative ultrasound (eBMD). Next, meta-analysis identified 13 bone fracture loci in ~1.2M individuals, which were also associated with BMD. We then developed STARLinG, a method to identify Target Genes from cell-specific genomic landscape features, including chromatin conformation and accessible chromatin sites. STARLinG identified Target Genes that were strongly enriched for genes known to influence bone density and strength (maximum odds ratio = 58, P = 10-75). We next performed rapid throughput skeletal phenotyping of 126 knockout mice lacking eBMD Target Genes and showed that these mice had an increased frequency of abnormal skeletal phenotypes compared to 526 unselected lines (P