Integrating genome- wide association study with regulatory SNP annotations identified novel candidate genes for osteoporosis

Aims Osteoporosis (OP) is a metabolic bone disease, characterized by a decrease in bone mineral density (BMD). However, the research of regulatory variants has been limited for BMD. In this study, we aimed to explore novel regulatory genetic variants associated with BMD.Methods We conducted an integrative analysis of BMD genome- wide association study (GWAS) and regulatory single nucleotide polymorphism (rSNP) annotation information. Firstly, the dis-covery GWAS dataset and replication GWAS dataset were integrated with rSNP annotation database to obtain BMD associated SNP regulatory elements and SNP regulatory element -target gene (E -G) pairs, respectively. Then, the common genes were further subjected to HumanNet v2 to explore the biological effects.Results Through discovery and replication integrative analysis for BMD GWAS and rSNP annotation database, we identified 36 common BMD-associated genes for BMD irrespective of regula-tory elements, such as FAM3C (pdiscovery GWAS = 1.21 x 10-25, preplication GWAS = 1.80 x 10-12), CCDC170 (pdiscovery GWAS = 1.23 x 10-11, preplication GWAS = 3.22 x 10-9), and SOX6 (pdiscovery GWAS = 4.41 x 10-15, preplication GWAS = 6.57 x 10-14). Then, for the 36 common target genes, multiple gene ontology (GO) terms were detected for BMD such as positive regulation of cartilage development (p = 9.27 x 10-3) and positive regulation of chondrocyte differentiation (p = 9.27 x 10-3).Conclusion We explored the potential roles of rSNP in the genetic mechanisms of BMD and identified multiple candidate genes. Our study results support the implication of regulatory genetic variants in the development of OP.