Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study

@article{citeulike:2786404, abstract = {SummaryBackground Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density.Methods In this genome-wide association study, we identified the most promising of 314[punctuation space]075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies.Findings We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5×10-8). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6·3×10-12 for lumbar spine and p=1·9×10-4 for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1·3, 95\% CI 1·09-1·52, p=0·002) and osteoporosis (OR 1·3, 1·08-1·63, p=0·008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7·6×10-10 for lumbar spine and p=3·3×10-8 for femoral neck) and increased risk of osteoporosis (OR 1·2, 95\% CI 1·01-1·42, p=0·038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3·0×10-6). 1883 (22\%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2·3×10-17). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1·3, 1·08-1·63, p=0·006) and this effect was independent of bone mineral density.Interpretation Two gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.Funding Wellcome Trust, European Commission, NWO Investments, Arthritis Research Campaign, Chronic Disease Research Foundation, Canadian Institutes of Health Research, European Society for Clinical and Economic Aspects of Osteoporosis, Genome Canada, Genome Queb\'{e}c, Canada Research Chairs, National Health and Medical Research Council of Australia, and European Union.}, author = {Richards, J. B. and Rivadeneira, F. and Inouye, M. and Pastinen, T. M. and Soranzo, N. and Wilson, S. G. and Andrew, T. and Falchi, M. and Gwilliam, R. and Ahmadi, K. R. and Valdes, A. M. and Arp, P. and Whittaker, P. and Verlaan, D. J. and Jhamai, M. and Kumanduri, V. and Moorhouse, M. and van Meurs, J. B. and Hofman, A. and Pols, H. A. P. and Hart, D. and Zhai, G. and Kato, B. S. and Mullin, B. H. and Zhang, F. and Deloukas, P. and Uitterlinden, A. G. and Spector, T. D. }, citeulike-article-id = {2786404}, doi = {10.1016/S0140-6736(08)60599-1}, journal = {The Lancet}, number = {9623}, pages = {1505--1512}, posted-at = {2008-05-12 05:51:22}, priority = {2}, title = {Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study}, url = {http://dx.doi.org/10.1016/S0140-6736(08)60599-1}, volume = {371} }

TY - JOUR ID - citeulike:2786404 L3 - citeulike-article-id:2786404 TI - Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study JF - The Lancet VL - 371 IS - 9623 SP - 1505 EP - 1512 N2 - SummaryBackground Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density.Methods In this genome-wide association study, we identified the most promising of 314[punctuation space]075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies.Findings We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5×10-8). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6·3×10-12 for lumbar spine and p=1·9×10-4 for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1·3, 95% CI 1·09-1·52, p=0·002) and osteoporosis (OR 1·3, 1·08-1·63, p=0·008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7·6×10-10 for lumbar spine and p=3·3×10-8 for femoral neck) and increased risk of osteoporosis (OR 1·2, 95% CI 1·01-1·42, p=0·038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3·0×10-6). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2·3×10-17). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1·3, 1·08-1·63, p=0·006) and this effect was independent of bone mineral density.Interpretation Two gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.Funding Wellcome Trust, European Commission, NWO Investments, Arthritis Research Campaign, Chronic Disease Research Foundation, Canadian Institutes of Health Research, European Society for Clinical and Economic Aspects of Osteoporosis, Genome Canada, Genome Quebéc, Canada Research Chairs, National Health and Medical Research Council of Australia, and European Union. AU - Richards, JB AU - Rivadeneira, F AU - Inouye, M AU - Pastinen, TM AU - Soranzo, N AU - Wilson, SG AU - Andrew, T AU - Falchi, M AU - Gwilliam, R AU - Ahmadi, KR AU - Valdes, AM AU - Arp, P AU - Whittaker, P AU - Verlaan, DJ AU - Jhamai, M AU - Kumanduri, V AU - Moorhouse, M AU - van Meurs, JB AU - Hofman, A AU - Pols, HAP AU - Hart, D AU - Zhai, G AU - Kato, BS AU - Mullin, BH AU - Zhang, F AU - Deloukas, P AU - Uitterlinden, AG AU - Spector, TD UR - http://dx.doi.org/10.1016/S0140-6736(08)60599-1 ER -