Oei L., Estrada K., Duncan EL., Christiansen C., Liu C-T., Langdahl BL., Obermayer-Pietsch B., Riancho JA., Prince RL., van Schoor NM., McCloskey E., Hsu Y-H., Evangelou E., Ntzani E., Evans DM., Alonso N., Husted LB., Valero C., Hernandez JL., Lewis JR., Kaptoge SK., Zhu K., Cupples LA., Medina-Gómez C., Vandenput L., Kim GS., Lee SH., Castaño-Betancourt MC., Oei EHG., Martinez J., Daroszewska A., van der Klift M., Mellström D., Herrera L., Karlsson MK., Hofman A., Ljunggren O., Pols HAP., Stolk L., van Meurs JBJ., Ioannidis JPA., Zillikens MC., Lips P., Karasik D., Uitterlinden AG., Styrkarsdottir U., Brown MA., Koh J-M., Richards JB., Reeve J., Ohlsson C., Ralston SH., Kiel DP., Rivadeneira F.

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 2,666 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, 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<5x10-8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6 x 10-8. However, the association was not significant across 5,720 cases and 21,791 controls from 14 studies. Fixed-effects meta analyses 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 are needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

Genome-wide Association Study for Radiographic Vertebral Fractures: A Potential Role for the 16q24 BMD Locus versus Lessons Learned from Challenging Phenotype Definition.

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