title: Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study.
abstract: BACKGROUND
  Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density.
  
  
  METHODS
  In this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies.
  
  
  RESULTS
  We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5x10(-8)). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6.3x10(-12) for lumbar spine and p=1.9x10(-4) for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1.3, 95% CI 1.09-1.52, p=0.002) and osteoporosis (OR 1.3, 1.08-1.63, p=0.008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7.6x10(-10) for lumbar spine and p=3.3x10(-8) for femoral neck) and increased risk of osteoporosis (OR 1.2, 95% CI 1.01-1.42, p=0.038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3.0x10(-6)). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2.3x10(-17)). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1.3, 1.08-1.63, p=0.006) and this effect was independent of bone mineral density.
  
  
  CONCLUSIONS
  Two gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: J B
authors.initials: JB
authors.lastname: Richards
authors.forename: F
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: M
authors.initials: M
authors.lastname: Inouye
authors.forename: T M
authors.initials: TM
authors.lastname: Pastinen
authors.forename: N
authors.initials: N
authors.lastname: Soranzo
authors.forename: S G
authors.initials: SG
authors.lastname: Wilson
authors.forename: T
authors.initials: T
authors.lastname: Andrew
authors.forename: M
authors.initials: M
authors.lastname: Falchi
authors.forename: R
authors.initials: R
authors.lastname: Gwilliam
authors.forename: K R
authors.initials: KR
authors.lastname: Ahmadi
authors.forename: A M
authors.initials: AM
authors.lastname: Valdes
authors.forename: P
authors.initials: P
authors.lastname: Arp
authors.forename: P
authors.initials: P
authors.lastname: Whittaker
authors.forename: D J
authors.initials: DJ
authors.lastname: Verlaan
authors.forename: M
authors.initials: M
authors.lastname: Jhamai
authors.forename: V
authors.initials: V
authors.lastname: Kumanduri
authors.forename: M
authors.initials: M
authors.lastname: Moorhouse
authors.forename: J B
authors.initials: JB
authors.lastname: van Meurs
authors.forename: A
authors.initials: A
authors.lastname: Hofman
authors.forename: H A P
authors.initials: HA
authors.lastname: Pols
authors.forename: D
authors.initials: D
authors.lastname: Hart
authors.forename: G
authors.initials: G
authors.lastname: Zhai
authors.forename: B S
authors.initials: BS
authors.lastname: Kato
authors.forename: B H
authors.initials: BH
authors.lastname: Mullin
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.forename: P
authors.initials: P
authors.lastname: Deloukas
authors.forename: A G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: T D
authors.initials: TD
authors.lastname: Spector
mesh_terms: D000483:Alleles; D015519:Bone Density / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11; D002898:Chromosomes, Human, Pair 8; D005260:Female; D050723:Fractures, Bone / Q000209:etiology*; D015870:Gene Expression; D005819:Genetic Markers; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008159:Lumbar Vertebrae; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000150:complications / Q000235:genetics*; D053244:Osteoprotegerin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D053244:Osteoprotegerin; C506030:TNFRSF11B protein, human