Systematic analysis of polymorphisms and linkage dsequilibrium in the osteoporosis susceptibility genes

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To clarify the genomic linkage of polymorphisms in the candidate gene loci of osteoporosis susceptibility genes, 12 candidate gene loci were selected through our original investigation of large scale single nucleotide polymorphism (SNP) association study using thousands of population subjects. By extracting multiple useful SNPs distributing throughout and beyond the loci in some cases, we analyzed linkage disequilibrium (LD) of those loci. Analyzed loci were the vitamin D binding protein gene (DBP), interleukin-1 receptor associated kinase 1 gene (IRAK1), tumor necrosis factor receptor-associated factor interacting protein gene (I-TRAF), gonadotropin releasing hormone gene (GnRH), glutaminyl-peptide cyclotransferase (QPCT), low density lipoprotein receptor-related protein 5 gene (LRP5), proopiomelanocortin gene (POMC), leukemia inhibitory factor receptor gene (LIFR), adducin 1 gene (ADD1), bone morphogenetic protein 8 gene (BMP8), heat shock protein 1A gene (HSPAIA), and the osteoclast-associated receptor gene (OSCAR). Analyses on some regions was difficult because of the existence of neighboring duplicated genes, like BMP8, however long range PCR usually solved the problem. By analyzing the indices of LD, D' and r2, we generally detected a single LD block covering the entire locus in each gene, however in several gene loci like LRP5 locus multiple block was observed. By clarifying the extent and the degree of LD in those loci, and selecting representative tag-SNPs in each LD blocks, we continued the association study using larger subject groups, to understand the genetic contribution of these candidate gene polymorphisms for bone mass determination.