Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density

Objectives to identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. Methods Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. potentially causal variants were identified using expression quantitative trait loci (eQtL) data from transiliac bone biopsies and bioinformatic studies. results A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (p=1.04×10) with a large effect size (or 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional Snps that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. Conclusion We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMd. Further studies are now in progress to validate this association and evaluate the underlying mechanism. IntrOduCtIOn Osteoporosis is a common disease with a strong genetic component. It is characterised by low bone mineral density (BMD), deterioration in the microstructural architecture of bone and an increased risk of fragility fractures. Vertebral fractures are an important complication of osteoporosis. They are characterised by loss of height and deformity of the affected vertebrae and associated with increased risk of other fractures. It has been estimated that between 8% and 30% of patients with radiological evidence of vertebral fractures (so-called morphometric fractures) come to medical attention for reasons that are incompletely understood. 4 In contrast, patients with vertebral fractures that come to medical attention because of symptoms such as back pain, kyphosis and height loss and are defined as having clinical vertebral fractures. Clinical vertebral fractures are associated with a markedly increased risk of future fractures and increased mortality. Major advances have been made in identifying genetic variants that regulate BMD, and some variants have also been identified that predispose to non-vertebral fractures. However, the genetic determinants of vertebral fractures are poorly understood. A previous genome-wide association study (GWAS) published by Oei and colleagues involving a discovery cohort of 8717 cases and 21 793 controls failed to identify any significant genetic predictors of radiographic vertebral fracture at a genome-wide significant level. However, in this study, the vertebral fractures were to cite: Alonso n, Estrada K, Albagha oME, et al. Ann Rheum Dis 2018;77:378–385. Handling editor tore K Kvien ► Additional material is published online only. to view please visit the journal online (http:// dx. doi. org/ 10. 1136/ annrheumdis2017212469). For numbered affiliations see end of article. Correspondence to professor Stuart H ralston, rheumatology and Bone disease Unit, Centre for Genomic and Experimental Medicine, IGMM University of Edinburgh, Western General Hospital, Edinburgh EH4 2xU, UK; stuart. ralston@ ed. ac. uk received 29 September 2017 Accepted 1 november 2017 published online First 23 november 2017