Identification of novel potentially pleiotropic variants associated with osteoporosis and obesity using the cFDR method

Abstract

Context: Genome-wide association studies (GWASs) have been successful in identifying loci associated with osteoporosis and obesity. However, the findings explain only a small fraction of the total genetic variance. Objective: The aim of this study was to identify novel pleiotropic genes important in osteoporosis and obesity. Design and Setting: A pleiotropic conditional false discovery rate method was applied to three independent GWAS summary statistics of femoral neck bone mineral density, body mass index, and waist-to-hip ratio. Next, differential expression analysis was performed for the potentially pleiotropic genes, and weighted genes coexpression network analysis (WGCNA) was conducted to identify functional connections between the suggested pleiotropic genes and known osteoporosis/obesity genes using transcriptomic expression data sets in osteoporosis/obesityrelated cells. Results: We identified seven potentially pleiotropic loci-rs3759579 (MARK3), rs2178950 (TRPS1), rs1473 (PUM1), rs9825174 (XXYLT1), rs2047937 (ZNF423), rs17277372 (DNM3), and rs335170 (PRDM6)-associated with osteoporosis and obesity. Of these loci, the PUM1 gene was differentially expressed in osteoporosis-related cells (B lymphocytes) and obesity-related cells (adipocytes). WGCNA showed that PUM1 positively interacted with several known osteoporosis genes (AKAP11, JAG1, and SPTBN1). ZNF423 was the highly connected intramodular hub gene and interconnected with 21 known osteoporosis-related genes, including JAG1, EN1, and FAM3C. Conclusions: Our study identified seven potentially pleiotropic genes associated with osteoporosis and obesity. The findings may provide new insights into a potential genetic determination and codetermination mechanism of osteoporosis and obesity.