Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture.
BACKGROUND
Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies.


OBJECTIVE
To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes.


METHODS
Large-scale meta-analysis of genome-wide association data.


METHODS
5 international, multicenter, population-based studies.


METHODS
Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands.


METHODS
Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures.


RESULTS
150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST.


CONCLUSIONS
Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded.


CONCLUSIONS
In this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD.
McGill University, Montreal, Quebec, Canada.
J Brent
JB
Richards
Fotini K
FK
Kavvoura
Fernando
F
Rivadeneira
Unnur
U
Styrkársdóttir
Karol
K
Estrada
Bjarni V
BV
Halldórsson
Yi-Hsiang
YH
Hsu
M Carola
MC
Zillikens
Scott G
SG
Wilson
Benjamin H
BH
Mullin
Najaf
N
Amin
Yurii S
YS
Aulchenko
L Adrienne
LA
Cupples
Panagiotis
P
Deloukas
Serkalem
S
Demissie
Albert
A
Hofman
Augustine
A
Kong
David
D
Karasik
Joyce B
JB
van Meurs
Ben A
BA
Oostra
Huibert A P
HA
Pols
Gunnar
G
Sigurdsson
Unnur
U
Thorsteinsdottir
Nicole
N
Soranzo
Frances M K
FM
Williams
Yanhua
Y
Zhou
Stuart H
SH
Ralston
Gudmar
G
Thorleifsson
Cornelia M
CM
van Duijn
Douglas P
DP
Kiel
Kari
K
Stefansson
André G
AG
Uitterlinden
John P A
JP
Ioannidis
Tim D
TD
Spector
D015519:Bone Density / Q000235:genetics*; D005260:Female; D050723:Fractures, Bone / Q000209:etiology / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010024:Osteoporosis / Q000150:complications / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors