Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus

Abstract

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey–Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey–Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han–Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p < 5 × 10−8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6×10−8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98–1.14; p = 0.17), displaying high degree of heterogeneity (I2=57%; Qhet p =0.0006). Under Han–Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

Quantitative imaging methods in osteoporosis

“…Phenotype definition is a cornerstone of epidemiological research into vertebral fracture risk to prevent bias hampering discoveries (171)(172)(173). Moreover, merely measuring vertebral heights in clinical practice frequently leads to misdiagnosis of fracture in non-osteoporotic conditions including Scheuermann's disease (174)(175)(176).…”

MECHANISMS IN ENDOCRINOLOGY: Genetics of human bone formation

“…These studies reported that VSP13B, UGT2B17 and an intergenic region within the 6p25.1 locus and 20q13.12 are associated with bone mass, osteoporosis or osteoporotic fractures (112,113,114,115,116,117).…”

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

“…However, the genetic determinants of vertebral fractures are poorly understood. A previous genome-wide association study (GWAS) published by Oei and colleagues21 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 defined simply on the basis of morphometric analysis of spinal radiographs.…”