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 discovery 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 regulatory elements, such as FAM3C (p(discovery GWAS) = 1.21 × 10(-25), p(replication GWAS) = 1.80 × 10(-12)), CCDC170 (p(discovery GWAS) = 1.23 × 10(-11), p(replication GWAS) = 3.22 × 10(-9)), and SOX6 (p(discovery GWAS) = 4.41 × 10(-15), p(replication GWAS) = 6.57 × 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 × 10(-3)) and positive regulation of chondrocyte differentiation (p = 9.27 × 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. Cite this article: Bone Joint Res 2023;12(2):147–154.