Genome wide association study of bone size yields eleven loci that also affect height, bone density, osteoarthritis and fractures

Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans, primarily performed to evaluate bone density and osteoporosis risk. Here, we report on a genome-wide association (GWA) study of DXA bone area of the hip and spine (N = 28,954). We found associations of common variants at eleven loci that replicate in samples of European and East Asian descent (N = 13,608 – 21,277). We also examined association of these markers with osteoarthritis and fractures in European samples (Ncases = 3,293 – 27,321). The strongest DXA area association is with a variant in the microRNA MIR196A2 gene at the HOXC locus that associates with reduced lumbar spine area (rs11614913[T], P = 2.3 × 10-42, ß = -0.090) and confers risk of hip fractures (P = 1.0 × 10-8, OR = 1.11). We demonstrate that the hip fracture risk allele [T] is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density. Eight DXA area loci associate with osteoarthritis, including rs143384 in the 5' UTR of the GDF5 gene and a missense variant in the COL11A1 gene (rs3753841[G], NP_001177638.1:p.Pro1284Leu). We also report a complex relationship between the variants associated with DXA area measures and height and bone mineral density (BMD). Overall design: Examination of mRNA expression in transfected HEK293T cells; MIR196A2 expression plasmids containing either the rs11614913[C] or rs11614913[T] alleles of MIR196A2, or empty vector plasmid deCODE genetics/Amgen Inc.