title: Contribution of the LRP5 gene to normal variation in peak BMD in women.
abstract: The role of the LRP5 gene in rare BMD-related traits has recently been shown. We tested whether variation in this gene might play a role in normal variation in peak BMD. Association between SNPs in LRP5 and hip and spine BMD was measured in 1301 premenopausal women. Only a small proportion of the BMD variation was attributable to LRP5 in our sample.
  
  
  BACKGROUND
  Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene have been implicated as the cause of multiple distinct BMD-related rare Mendelian phenotypes. We sought to examine whether the LRP5 gene contributes to the observed variation in peak BMD in the normal population.
  
  
  METHODS
  We genotyped 12 single nucleotide polymorphisms (SNPs) in LRP5 using allele-specific PCR and mass spectrometry methods. Linkage disequilibrium between the genotyped LRP5 SNPs was measured. We tested for association between these SNPs and both hip and spine BMD (adjusted for age and body weight) in 1301 healthy premenopausal women who took part in a sibling pair study aimed at identifying the genes underlying peak bone mass. Our study used both population-based (ANOVA) and family-based (quantitative transmission disequilibrium test) association methodology.
  
  
  CONCLUSIONS
  The linkage disequilibrium pattern and haplotype block structure within the LRP5 gene were consistent with that observed in other studies. Although significant evidence of association was found between LRP5 SNPs and both hip and spine BMD, only a small proportion of the total variation in these phenotypes was accounted for. The genotyped SNPs accounted for approximately 0.8% of the variation in femoral neck BMD and 1.1% of the variation in spine BMD. Results from our sample suggest that natural variation in and around LRP5 is not a major contributor to the observed variability in peak BMD at either the femoral neck or lumbar spine in white women.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. dkoller@iupui.edu
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Koller
authors.forename: Shoji
authors.initials: S
authors.lastname: Ichikawa
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Johnson
authors.forename: Dongbing
authors.initials: D
authors.lastname: Lai
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xuei
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.forename: P Michael
authors.initials: PM
authors.lastname: Conneally
authors.forename: Siu L
authors.initials: SL
authors.lastname: Hui
authors.forename: C Conrad
authors.initials: CC
authors.lastname: Johnston
authors.forename: Munro
authors.initials: M
authors.lastname: Peacock
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Econs
mesh_terms: D000328:Adult; D015519:Bone Density / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D026502:LDL-Receptor Related Proteins; D015810:Linkage Disequilibrium / Q000235:genetics; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D011973:Receptors, LDL