Identification of QTL genes for BMD variation using both linkage and gene-based association approaches

Hum Genet. 2011 Oct;130(4):539-46. doi: 10.1007/s00439-011-0972-2. Epub 2011 Mar 19.

Abstract

Low bone mineral density (BMD) is a risk factor for osteoporotic fracture with a high heritability. Previous large scale linkage study in Northern Chinese has identified four significant quantitative trait loci (QTL) for BMD variation on chromosome 2q24, 5q21, 7p21 and 13q21. We performed a replication study of these four QTL in 1,459 Southern Chinese from 306 pedigrees. Successful replication was observed on chromosome 5q21 for femoral neck BMD with a LOD score of 1.38 (nominal p value = 0.006). We have previously identified this locus in a genome scan meta-analysis of BMD variation in a white population. Subsequent QTL-wide gene-based association analysis in 800 subjects with extreme BMD identified CAST and ERAP1 as novel BMD candidate genes (empirical p value of 0.032 and 0.014, respectively). The associations were independently replicated in a Northern European population (empirical p value of 0.01 and 0.004 for CAST and ERAP1, respectively). These findings provide further evidence that 5q21 is a BMD QTL, and CAST and ERAP1 may be associated with femoral neck BMD variation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Asian Continental Ancestry Group
  • Bone Density / genetics*
  • Case-Control Studies
  • Chromosome Mapping
  • Chromosomes, Human, Pair 15 / genetics*
  • European Continental Ancestry Group
  • Female
  • Femur Neck / physiopathology*
  • Genetic Linkage*
  • Genetic Variation
  • Genotype
  • Humans
  • Lod Score
  • Male
  • Meta-Analysis as Topic
  • Middle Aged
  • Osteoporosis / genetics*
  • Pedigree
  • Quantitative Trait Loci*