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Bone mineral density (BMD) achieved during young adulthood (peak BMD) is one of the major determinants of osteoporotic fracture in later life. Genetic variants associated with BMD have been identified by three recent genome-wide association studies. The most significant single-nucleotide polymorphisms (SNPs) from these studies were genotyped to test whether they were associated with peak BMD in premenopausal American women. Femoral neck and lumbar spine BMD were determined by dual-energy X-ray absorptiometry in two groups of premenopausal women: 1524 white women and 512 black women. In premenopausal white women, two SNPs in the C6orf97/ESR1 region were significantly associated with BMD (p < 4.8 x 10(-4)), with suggestive evidence for CTNNBL1 and LRP5 (p < .01). Evidence of association with one of the two SNPs in the C6orf97/ESR1 region also was observed in premenopausal black women. Furthermore, SNPs in SP7 and a chromosome 4 intergenic region showed suggestive association with BMD in black women. Detailed analyses of additional SNPs in the C6orf97/ESR1 region revealed multiple genomic blocks independently associated with femoral neck and lumbar spine BMD. Findings in the three published genome-wide association studies were replicated in independent samples of premenopausal American women, suggesting that genetic variants in these genes or regions contribute to peak BMD in healthy women in various populations.

Background: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency., Methods: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants., Findings: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile., Interpretation: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency., Funding: Full funding sources listed at end of paper (see Acknowledgments)., (Copyright 2010 Elsevier Ltd. All rights reserved.)