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

Abstract

AimsOsteoporosis (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.MethodsWe 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.ResultsThrough 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 (pdiscovery GWAS = 1.21 × 10-25, preplication GWAS = 1.80 × 10-12), CCDC170 (pdiscovery GWAS = 1.23 × 10-11, preplication GWAS = 3.22 × 10-9), and SOX6 (pdiscovery GWAS = 4.41 × 10-15, preplication 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).ConclusionWe 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.

Interleukin-19 promotes bone resorption by suppressing osteoprotegerin expression in BMSCs in a lipopolysaccharide-induced bone loss mouse model

“…36 Moreover, global IL-19 deletion had no effect on bone formation, but suppressed osteoclastogenesis in the LPStreated mice group. Nevertheless, we did not detect the cytokines associated with C57BL/6 mice, 41 and it remains to be further explored whether there is a decrease in cytokines such as CCL3, TNF-α, and CCL4 similar to that in BALB/c mice.…”

“…In vitro experiments have shown that IL-19 inhibits osteoblast differentiation by suppressing NF-κB and 38 kD mitogen-activated protein kinases (p38MAPK) activation, as well as c-Fos expression, in the mouse macrophage-like cell line RAW264.7. 41 , 49 We examined the levels of RANKL and OPG in peripheral blood and bone marrow of two groups of mice. In the LPS-induced bone loss mouse model, there was no significant change in RANKL content in serum and femoral bone marrow suspension, but OPG content was significantly reduced.…”

The association between selenium and bone health: a meta-analysis

“…7 With an ageing population, it is predicted that OP-related healthcare burdens will increase rapidly. 8 Multiple environmental and genetic factors play a role in OP, [9][10][11] but there is still an urgent need to determine more modifiable potential risk factors for OP.…”