A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus.
Oei L., Hsu Y-H., Styrkarsdottir U., Eussen BH., de Klein A., Peters MJ., Halldorsson B., Liu C-T., Alonso N., Kaptoge SK., Thorleifsson G., Hallmans G., Hocking LJ., Husted LB., Jameson KA., Kruk M., Lewis JR., Patel MS., Scollen S., Svensson O., Trompet S., van Schoor NM., Zhu K., Buckley BM., Cooper C., Ford I., Goltzman D., González-Macías J., Langdahl BL., Leslie WD., Lips P., Lorenc RS., Olmos JM., Pettersson-Kymmer U., Reid DM., Riancho JA., Slagboom PE., Garcia-Ibarbia C., Ingvarsson T., Johannsdottir H., Luben R., Medina-Gómez C., Arp P., Nandakumar K., Palsson ST., Sigurdsson G., van Meurs JBJ., Zhou Y., Hofman A., Jukema JW., Pols HAP., Prince RL., Cupples LA., Marshall CR., Pinto D., Sato D., Scherer SW., Reeve J., Thorsteinsdottir U., Karasik D., Richards JB., Stefansson K., Uitterlinden AG., Ralston SH., Ioannidis JPA., Kiel DP., Rivadeneira F., Estrada K.
BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. AIM: To identify CNVs associated with osteoporotic bone fracture risk. METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.