Genome-wide Copy Number Variation Study Associated With Hip Bone Size In Chinese Population

Osteoporosis characterized by low bone mineral density (BMD), is the most prevalent metabolic bone disease among older people, increases risk for low trauma hip fracture (HF) that is associated with high morbidity and mortality. Especially in recent years, increased aging Chinese population attracts more attention to HF in China. Hip bone size (BS) has been identified as one of the key measurable risk factors for HF. Although hip BS is highly genetically determined, genetic factors underlying the trait are still poorly defined.Copy number variation (CNV) has been identified to be associated with human complex diseases. CNVs may alter gene dosage, disrupt coding sequences, or exert long-range positional effects on the gene expression pattern outside the CNV region, consequently leading to varied phenotypes. Studies showed that lower copy number of the CCL3L1, FCGR3B and DEFB4 genes occurred in susceptive individuals who were predisposed to diseases AIDS, immunologically mediated glomerulonephritis and Crohn disease, respectively. Recently, our group performed the genome-wide CNV association studies on phenotypes related to esteoporosis and indentified several new candidate genes, UGT2B17 and VPS13B. However, the effect of CNVs on hip bone size is unknown.Here, we performed the first genome-wide copy number variation (CNV) association analysis for hip BS in 1627 Chinese Han subjects using Affymetrix GeneChip Human Mapping SNP6.0 assay kit and replicated our most significant results in 2286 unrelated US Caucasians sample.We found that a copy number polymorphism (CNP267) located at chromosome 2q12.2 was significantly associated with hip BS in both initial Chinese and replicate Caucasian samples with p values of 4.73E-03 and 5.66E-03, respectively. An important candidate gene, four and a half LIM domains 2 (FHL2), was detected in CNP267 regions, which plays important roles in bone metabolism by binding to several bone formation regulator, such as insulin-like growth factor-binding protein 5 (IGFBP-5) and androgen receptor (AR). We also found an another CNP, CNP1q44, which although was only significant in Chinese sample (P=1.05E-03), it covered the gene consortin, connexin sorting protein (CNST) which might be important to bone via its function in targeting connexins, especially, connexin 43.In conclusion, we indentified CNP182 and CNP267 as two genomic markers for hip bone size.