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

Accepted version
Peer-reviewed

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Authors

Alonso, Nerea 
Estrada, Karol 
Albagha, Omar ME 
Herrera, Lizbeth 
Reppe, Sjur 

Abstract

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=1.04×10-9) 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.

Description

Keywords

bone mineral density, gene polymorphism, osteoporosis, Aged, Aged, 80 and over, Bone Density, Chromosomes, Human, Pair 2, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Middle Aged, Osteoporotic Fractures, Polymorphism, Single Nucleotide, Postmenopause, Quantitative Trait Loci, Spinal Fractures

Journal Title

Ann Rheum Dis

Conference Name

Journal ISSN

0003-4967
1468-2060

Volume Title

77

Publisher

Elsevier BV
Sponsorship
Medical Research Council (G1000143)
Medical Research Council (G0401527)
MRC (T05028)
Medical Research Council (MR/N003284/1)
Medical Research Council (G0401527/1)
Cancer Research Uk (None)