Identifying potentially common genes between dyslipidemia and osteoporosis using novel analytical approaches

Xu Lin, Cheng Peng, Jonathan Greenbaum, Zhang-Fang Li, Ke-Hao Wu, Zeng-Xin Ao, Tong Zhang, Jie Shen, Hong-Wen Deng

Dyslipidemia (DL) is closely related to osteoporosis (OP), while the exact common genetic mechanisms are still largely unknown. We proposed to use novel genetic analysis methods with pleiotropic information to identify potentially novel and/or common genes for the potential shared pathogenesis associated with OP and/or DL. We assessed the pleiotropy between plasma lipid (PL) and femoral neck bone mineral density (FNK BMD). We jointly applied the conditional false discovery rate (cFDR) method and the genetic analysis incorporating pleiotropy and annotation (GPA) method to the summary statistics provided by genome-wide association studies (GWASs) of FNK BMD (n = 49,988) and PL (n = 188,577) to identify potentially novel and/or common genes for BMD/PL. We found strong pleiotropic enrichment between PL and FNK BMD. Two hundred and forty-five PL SNPs were identified as potentially novel SNPs by cFDR and GPA. The corresponding genes were enriched in gene ontology (GO) terms "phospholipid homeostasis" and "chylomicron remnant clearance". Three SNPs (rs2178950, rs9939318, and rs9368716) might be the pleiotropic ones and the corresponding genes NLRC5 (rs2178950) and TRPS1 (rs9939318) were involved in NF-κB signaling pathway and Wnt signaling pathway as well as inflammation and innate immune processes. Our study validated the pleiotropy between PL and FNK BMD, and corroborated the reliability and high-efficiency of cFDR and GPA methods in further analyses of existing GWASs with summary statistics. We identified potentially common and/or novel genes for PL and/or FNK BMD, which may provide new insight and direction for further research.