TY - JOUR
T1 - Collaborative Meta-analysis: Associations of 150 Candidate Genes With Osteoporosis and Osteoporotic Fracture
AU - Richards, JB
AU - Kavvoura, FK
AU - Rivadeneira, Fernando
AU - Styrkarsdottir, U
AU - Estrada Gil, Karol
AU - Halldorsson, BV
AU - Hsu, YH
AU - Zillikens, M.C.
AU - Wilson, SG
AU - Mullin, BH
AU - Amin, Najaf
AU - Aulchenko, YS
AU - Cupples, LA
AU - Deloukas, P
AU - Demissie, S
AU - Hofman, Bert
AU - Kong, A
AU - Karasik, D
AU - van Meurs, Joyce
AU - Oostra, Ben
AU - Pols, Huib
AU - Sigurdsson, G
AU - Thorsteinsdottir, U
AU - Soranzo, N
AU - Williams, FMK
AU - Zhou, YH
AU - Ralston, SH
AU - Thorleifsson, G
AU - Duijn, Cornelia
AU - Kiel, DP
AU - Stefansson, K
AU - Uitterlinden, André
AU - Ioannidis, JPA
AU - Spector, TD
PY - 2009
Y1 - 2009
N2 - Background: Osteoporosis 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. Objective: To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes. Design: Large-scale meta-analysis of genome-wide association data. Setting: 5 international, multicenter, population-based studies. Participants: Data 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. Measurements: Systematic 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. Results: 150 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. Limitation: Only 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. Conclusion: In 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.
AB - Background: Osteoporosis 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. Objective: To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes. Design: Large-scale meta-analysis of genome-wide association data. Setting: 5 international, multicenter, population-based studies. Participants: Data 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. Measurements: Systematic 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. Results: 150 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. Limitation: Only 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. Conclusion: In 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.
M3 - Article
SN - 0003-4819
VL - 151
SP - 528-U32
JO - Annals of Internal Medicine
JF - Annals of Internal Medicine
IS - 8
ER -