Multiple genetic loci for bone mineral density and fractures

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field 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...

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Bibliographic Details
Published in:New England Journal of Medicine
Main Authors: Styrkarsdottir, Unnur, Halldorsson, Bjarni V, Gretarsdottir, Solveig, Gudbjartsson, Daniel F, Walters, G Bragi, Ingvarsson, Thorvaldur, Jonsdottir, Thorbjorg, Saemundsdottir, Jona, Center, Jacqueline R, Nguyen, Tuan V, Bagger, Yu, Gulcher, Jeffrey R, Eisman, John A, Christiansen, Claus, Sigurdsson, Gunnar, Kong, Augustine, Thorsteinsdottir, Unnur, Stefansson, Kari
Other Authors: deCODE Genetics, Reykjavik, Iceland.
Format: Article in Journal/Newspaper
Language:English
Published: Massachusetts Medical Society 2009
Subjects:
Adolescent
Adult
Aged
80 and over
Australia
Bone Density
Denmark
Estrogen Receptor alpha
Female
Fractures
Bone
Genotype
Humans
Iceland
Linear Models
Male
Middle Aged
Osteoporosis
Osteoprotegerin
Polymorphism
Single Nucleotide
Quantitative Trait Loci
RANK Ligand
Online Access:http://hdl.handle.net/2336/84841
https://doi.org/10.1056/NEJMoa0801197
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Summary:To access publisher full text version of this article. Please click on the hyperlink in Additional Links field 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-kappaB 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-kappaB 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 ...

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