Abstract
By integrating the multilevel biological evidence and bioinformatics analyses, the present study represents a systemic endeavor to identify BMD-associated genes and their roles in skeletal metabolism. INTRODUCTION: Single-nucleotide polymorphism (SNP)-based genome-wide association studies (GWASs) have already identified about 100 loci associated with bone mineral density (BMD), but these loci only explain a small proportion of heritability to osteoporosis risk. In the present study, we performed a gene-based analysis of the largest GWASs in the bone field to identify additional BMD-associated genes. METHODS: BMD-associated genes were identified by combining the summary statistic P values of SNPs across individual genes in the two consecutive meta-analyses of GWASs from the Genetic Factors for Osteoporosis (GEFOS) studies. The potential functionality of these genes to bone was partially assessed by differential gene expression analysis. Additionally, the consistency of the identification of potential bone mineral density (BMD)-associated variants were evaluated by estimating the correlation of the P values of the same single-nucleotide polymorphisms (SNPs)/genes between the two consecutive Genetic Factors for Osteoporosis Studies (GEFOS) with largely overlapping samples. RESULTS: Compared to the SNP-based analysis, the gene-based strategy identified additional BMD-associated genes with genome-wide significance and increased their mutual replication between the two GEFOS datasets. Among these BMD-associated genes, three novel genes (UBTF, AAAS, and C11orf58) were partially validated at the gene expression level. The correlation analysis presented a moderately high between-study consistency of potential BMD-associated variants. CONCLUSIONS: Gene-based analysis as a supplementary strategy to SNP-based genome-wide association studies, when applied here, is shown that it helped identify some novel BMD-associated genes. In addition to its empirically increased statistical power, gene-based analysis also provides a higher testing stability for identification of BMD genes.