title: Identification of QTL genes for BMD variation using both linkage and gene-based association approaches.
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.
authors.affiliation: Department of Medicine, The University of Hong Kong, Lab Block, 21 Sassoon Road, Hong Kong, Hong Kong.
authors.forename: Gloria Hoi-Yee
authors.initials: GH
authors.lastname: Li
authors.forename: Ching-Lung
authors.initials: CL
authors.lastname: Cheung
authors.forename: Su-Mei
authors.initials: SM
authors.lastname: Xiao
authors.forename: Kam-Shing
authors.initials: KS
authors.lastname: Lau
authors.forename: Yi
authors.initials: Y
authors.lastname: Gao
authors.forename: Cora H
authors.initials: CH
authors.lastname: Bow
authors.forename: Qing-Yang
authors.initials: QY
authors.lastname: Huang
authors.forename: Pak-Chung
authors.initials: PC
authors.lastname: Sham
authors.forename: Annie Wai-Chee
authors.initials: AW
authors.lastname: Kung
mesh_terms: D000328:Adult; D044466:Asian People; D015519:Bone Density / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D005260:Female; D005272:Femur Neck / Q000503:physiopathology*; D008040:Genetic Linkage; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics*; D010375:Pedigree; D040641:Quantitative Trait Loci; D044465:White People