Multiple genetic loci for bone mineral density and fractures.
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 underlying osteoporosis.
Styrkarsdottir
Unnur
U
deCODE Genetics, Reykjavik, Iceland.
Halldorsson
Bjarni V
BV
Gretarsdottir
Solveig
S
Gudbjartsson
Daniel F
DF
Walters
G Bragi
GB
Ingvarsson
Thorvaldur
T
Jonsdottir
Thorbjorg
T
Saemundsdottir
Jona
J
Center
Jacqueline R
JR
Nguyen
Tuan V
TV
Bagger
Yu
Y
Gulcher
Jeffrey R
JR
Eisman
John A
JA
Christiansen
Claus
C
Sigurdsson
Gunnar
G
Kong
Augustine
A
Thorsteinsdottir
Unnur
U
Stefansson
Kari
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D015519:Bone Density / Q000235:genetics*; D003718:Denmark; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D050723:Fractures, Bone / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007055:Iceland; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics*; D053244:Osteoprotegerin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D053245:RANK Ligand / Q000235:genetics*
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D053244:Osteoprotegerin; D053245:RANK Ligand; C505688:TNFSF11 protein, human