Multiple genetic loci for bone mineral density and fractures

Styrkarsdottir, U; Halldorsson, BV; Gretarsdottir, S; Gudbjartsson, DF; Walters, GB; Ingvarsson, T; Jonsdottir, T; Saemundsdottir, J; Center, JR; Nguyen, TV; Bagger, Y; Gulcher, JR; Eisman, JA; Christiansen, C; Sigurdsson, G; Kong, A; Thorsteinsdottir, U; Stefansson, K

Multiple genetic loci for bone mineral density and fractures

Styrkarsdottir, U Halldorsson, BV Gretarsdottir, S Gudbjartsson, DF Walters, GB Ingvarsson, T Jonsdottir, T Saemundsdottir, J Center, JR Nguyen, TV

Bagger, Y Gulcher, JR Eisman, JA Christiansen, C Sigurdsson, G Kong, A Thorsteinsdottir, U Stefansson, K

Permalink

Publication Type:: Journal Article
Citation:: New England Journal of Medicine, 2008, 358 (22), pp. 2355 - 2365
Issue Date:: 2008-05-29

Closed Access

	Filename	Description	Size
	2013005882OK.pdf		793.41 kB	Adobe PDF	View/Open

Copyright Clearance Process

Recently Added
In Progress
Closed Access

This item is closed access and not available.

Full metadata record

Field	Value	Language
dc.contributor.author	Styrkarsdottir, U	en_US
dc.contributor.author	Halldorsson, BV	en_US
dc.contributor.author	Gretarsdottir, S	en_US
dc.contributor.author	Gudbjartsson, DF	en_US
dc.contributor.author	Walters, GB	en_US
dc.contributor.author	Ingvarsson, T	en_US
dc.contributor.author	Jonsdottir, T	en_US
dc.contributor.author	Saemundsdottir, J	en_US
dc.contributor.author	Center, JR	en_US
dc.contributor.author	Nguyen, TV https://orcid.org/0000-0002-3246-6281	en_US
dc.contributor.author	Bagger, Y	en_US
dc.contributor.author	Gulcher, JR	en_US
dc.contributor.author	Eisman, JA	en_US
dc.contributor.author	Christiansen, C	en_US
dc.contributor.author	Sigurdsson, G	en_US
dc.contributor.author	Kong, A	en_US
dc.contributor.author	Thorsteinsdottir, U	en_US
dc.contributor.author	Stefansson, K	en_US
dc.date.issued	2008-05-29	en_US
dc.identifier.citation	New England Journal of Medicine, 2008, 358 (22), pp. 2355 - 2365	en_US
dc.identifier.issn	0028-4793	en_US
dc.identifier.uri	http://hdl.handle.net/10453/28797
dc.description.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-κB 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-κB 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. Copyright © 2008 Massachusetts Medical Society.	en_US
dc.relation.ispartof	New England Journal of Medicine	en_US
dc.relation.isbasedon	10.1056/NEJMoa0801197	en_US
dc.subject.classification	General & Internal Medicine	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Osteoporosis	en_US
dc.subject.mesh	Estrogen Receptor alpha	en_US
dc.subject.mesh	Linear Models	en_US
dc.subject.mesh	Bone Density	en_US
dc.subject.mesh	Genotype	en_US
dc.subject.mesh	Polymorphism, Single Nucleotide	en_US
dc.subject.mesh	Quantitative Trait Loci	en_US
dc.subject.mesh	Adolescent	en_US
dc.subject.mesh	Adult	en_US
dc.subject.mesh	Aged	en_US
dc.subject.mesh	Aged, 80 and over	en_US
dc.subject.mesh	Middle Aged	en_US
dc.subject.mesh	Australia	en_US
dc.subject.mesh	Iceland	en_US
dc.subject.mesh	Denmark	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Fractures, Bone	en_US
dc.subject.mesh	RANK Ligand	en_US
dc.subject.mesh	Osteoprotegerin	en_US
dc.title	Multiple genetic loci for bone mineral density and fractures	en_US
dc.type	Journal Article
utslib.citation.volume	22	en_US
utslib.citation.volume	358	en_US
utslib.for	110311 Medical Genetics (excl. Cancer Genetics)	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.issue	22	en_US
pubs.publication-status	Published	en_US
pubs.volume	358	en_US

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-κB 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-κB 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. Copyright © 2008 Massachusetts Medical Society.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/28797