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Published at www.nejm.org April 29, 2008 (10.1056/NEJMoa0801197)

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ABSTRACT

Background Bone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify sequence variants associated with bone mineral density and fracture.

Methods We performed a quantitative trait analysis of data from 5861 Icelandic subjects (the discovery set), testing for an association between 301,019 single-nucleotide polymorphisms (SNPs) and bone mineral density of the hip and lumbar spine. We then tested for an association between 74 SNPs (most of which were implicated in the discovery set) at 32 loci in replication sets of Icelandic, Danish, and Australian subjects (4165, 2269, and 1491 subjects, respectively).

Results Sequence variants in five genomic regions were significantly associated with bone mineral density in the discovery set and were confirmed in the replication sets (combined P values, 1.2x10^–7 to 2.0x10^–21). Three regions are close to or within genes previously shown to be important to the biologic characteristics of bone: the receptor activator of nuclear factor-B ligand gene (RANKL) (chromosomal location, 13q14), the osteoprotegerin gene (OPG) (8q24), and the estrogen receptor 1 gene (ESR1) (6q25). The two other regions are close to the zinc finger and BTB domain containing 40 gene (ZBTB40) (1p36) and the major histocompatibility complex region (6p21). The 1p36, 8q24, and 6p21 loci were also associated with osteoporotic fractures, as were loci at 18q21, close to the receptor activator of the nuclear factor-B gene (RANK), and loci at 2p16 and 11p11.

Conclusions We have discovered common sequence variants that are consistently associated with bone mineral density and with low-trauma fractures in three populations of European descent. Although these variants alone are not clinically useful in the prediction of risk to the individual person, they provide insight into the biochemical pathways underlying osteoporosis.

Source Information

From deCODE Genetics (U.S., B.V.H., S.G., D.F.G., G.B.W., T.J., J.S., J.R.G., A.K., U.T., K.S.), Reykjavik University (B.V.H.), and University Hospital (G.S.) — all in Reykjavik, Iceland; Fjordungssjukrahusid Akureyri University Hospital, Akureyri, Iceland (T.I.); Garvan Institute of Medical Research, Sydney (J.R.C., T.V.N., J.A.E.); and Center for Clinical and Basic Research, Ballerup (Y.B.), and Nordic Bioscience, Herlev (C.C.) — both in Denmark.

This article (10.1056/NEJMoa0801197) was published at www.nejm.org on April 29, 2008. It will appear in the May 29 issue of the Journal.

Address reprint requests to Dr. Stefansson at deCODE Genetics, Sturlugata 8, IS-101, Reykjavik, Iceland, or at kari.stefansson{at}decode.is.

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