Vertebral fractures are the most common complication of osteoporosis, but little is known about the genetic determinants of susceptibility. Here we present the results of a genome wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with replication in 667 cases and 2105 controls. A locus tagged by a less frequent variant (rs10190845, A-allele MAF=0.05) was identified on chromosome 2q13 as a strong predictor of clinical vertebral fracture (P=1.27×10−8) with a large effect size (odds ratio 1.75, 95% CI 1.42.1). Three other loci were identified on chromosomes 1p31, 11q12 and 15q11, associated at suggestive level (P<5×10−6). All were novel loci that had not previously been associated with bone mineral density (BMD) or clinical fractures. Analysis of 71 variants that had been associated with spine BMD or fractures at a genome wide significant level in other studies identified eight that were significantly associated with vertebral fractures in the present study after Bonferroni correction (P<7×10−4). Bioinformatic analysis of the 2q13 locus identified several potentially functional SNPs which were associated with expression of the positional candidate genes TTL and SLC20A1 in whole bone tissue, none of which is known to play a role in bone biology. Our study illustrates that some predisposing variants for clinical vertebral fractures overlap with known genetic determinants of susceptibility to osteoporosis whereas others are unique. The study has cast new light on the genetic architecture of clinical vertebral fractures and has identified a variant with one of the largest effect sizes so far described in osteoporosis genetics.
14 May 2016 - 17 May 2016