Positional Cloning Identified ESR2, ESRRB, BMP4 and LTBP2 as the Candidate Genes for the Quantitative Trait Locus In Chromosome 14 for BMD variation

Abstract

Chromosome 14 has previously been linked to BMD variation in several genome-wide linkage studies. To replicate and fine-map the quantitative trait locus (QTL) influencing BMD in southern Chinese, a high-density linkage and association screen of chromosome 14ql3-32 was performed using high-density microsatellite markers in 306 extended southern Chinese families having a proband with BMD Z score<-1.28 (equivalent to lowest IOIh percentile of the population) at either hip or spine. Candidate genes were identified within the QTL with gene prioritization using the Endeavour programme. Genotyping of the candidate genes was performed with Tag SNPs in another cohort of 600 pairs of unrelated high (2 score >+l) and low BMD (Z score<-1.28) subjects. Maximum LOD score of 1.89 was detected at 69.2cM (34q23) for total hip BMD. LOD scores greater than 1.2 were detected at 14q21 for femoral neck BMD. 14q12-13 and 14q23 for trochanter BMD. Five candidate genes were identified within these regions, namely estrogen receptor p (ESIU), bone morphometric protein 4 (BMP4). estrogen-related receptor p (ESRRB), latent transforming growth factor beta binding protein 2 (LTBPZ), and transforming growth factor beta 3 (TGFB3). Significant association was detected with the following SNPs: TI213C, A110732G of ESR2, rs762642 and rs2071047 of BMP4, rs2980896, rs4903413 and rs12436385 of ERR2, rs2359141, rs3825709, rs228641 I. rs2043948 and rs7569 of LTBP2, 1~3917201 of TGFB3. Epistasis revealed significant gene-gene interaction between these genes which may be the underlying mechanism explaining the linkage peak. Our results identified multiple genes within the QTL in chromosome 14 that contribute to BMD variation in the general population. These results help in understanding the pathophysiology of low bone mass and osteoporosis.