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

• Published in: Human genetics 2011-10, Vol.130 (4), p.539-546
• Main Authors: Li, Gloria Hoi-Yee, Cheung, Ching-Lung, Xiao, Su-Mei, Lau, Kam-Shing, Gao, Yi, Bow, Cora H., Huang, Qing-Yang, Sham, Pak-Chung, Kung, Annie Wai-Chee
• Format: Article
• Language: English
• Subjects: Adult; Analysis; Asian Continental Ancestry Group; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Bone density; Bone Density - genetics; Bones; Case-Control Studies; Chromosome Mapping; Chromosomes, Human, Pair 15 - genetics; Classical genetics, quantitative genetics, hybrids; Density; Ethnicity; European Continental Ancestry Group; Family medical history; Female; Femur Neck - physiopathology; Fundamental and applied biological sciences. Psychology; Gene Function; Gene loci; Genes; Genetic Linkage; Genetic Variation; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Genomics; Genotype; Hormone replacement therapy; Human; Human Genetics; Humans; Lod Score; Male; Meta-Analysis as Topic; Metabolic Diseases; Metabolism; Metabolites; Methods, theories and miscellaneous; Middle Aged; Molecular Medicine; Original Investigation; Osteoporosis; Osteoporosis - genetics; Pedigree; Quantitative Trait Loci; Risk factors; Standard scores; Womens health
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-011-0972-2

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.