Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture.
Richards JB., Kavvoura FK., Rivadeneira F., Styrkársdóttir U., Estrada K., Halldórsson BV., Hsu Y-H., Zillikens MC., Wilson SG., Mullin BH., Amin N., Aulchenko YS., Cupples LA., Deloukas P., Demissie S., Hofman A., Kong A., Karasik D., van Meurs JB., Oostra BA., Pols HAP., Sigurdsson G., Thorsteinsdottir U., Soranzo N., Williams FMK., Zhou Y., Ralston SH., Thorleifsson G., van Duijn CM., Kiel DP., Stefansson K., Uitterlinden AG., Ioannidis JPA., Spector TD., Genetic Factors for Osteoporosis Consortium .
BackgroundOsteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies.ObjectiveTo assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes.DesignLarge-scale meta-analysis of genome-wide association data.Setting5 international, multicenter, population-based studies.ParticipantsData on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands.MeasurementsSystematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures.Results150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST.LimitationOnly common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded.ConclusionIn this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD.