An atlas of genetic influences on osteoporosis in humans and mice.
Morris JA., Kemp JP., Youlten SE., Laurent L., Logan JG., Chai RC., Vulpescu NA., Forgetta V., Kleinman A., Mohanty ST., Sergio CM., Quinn J., Nguyen-Yamamoto L., Luco A-L., Vijay J., Simon M-M., Pramatarova A., Medina-Gomez C., Trajanoska K., Ghirardello EJ., Butterfield NC., Curry KF., Leitch VD., Sparkes PC., Adoum A-T., Mannan NS., Komla-Ebri DSK., Pollard AS., Dewhurst HF., Hassall TAD., Beltejar M-JG., 23andMe Research Team None., Adams DJ., Vaillancourt SM., Kaptoge S., Baldock P., Cooper C., Reeve J., Ntzani EE., Evangelou E., Ohlsson C., Karasik D., Rivadeneira F., Kiel DP., Tobias JH., Gregson CL., Harvey NC., Grundberg E., Goltzman D., Adams DJ., Lelliott CJ., Hinds DA., Ackert-Bicknell CL., Hsu Y-H., Maurano MT., Croucher PI., Williams GR., Bassett JHD., Evans DM., Richards JB.
Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.