Identification Of Novel Variants For Osteoporosis And Pleiotropic Variants With Coronary Artery Disease Using Genome-Wide Bivariate Analysis

[Background and Objective]Osteoporosis(OP)is a chronic bone disease characterized by the decrease of bone mass and bone strength,as well as an increased fracture risk.Due to its high morbidity,mortality and huge medical cost,OP becomes a major public health problem worldwide.Identifing more genetic variants is important for the further exploration of OP’s pathogenesis,but according to the limitation of traditional GWAS,only a small number of variants were identified.Bone formation is very similar to the calcification of coronary artery,and close relationship has been found between OP and coronary artery disease(CAD).OP and CAD have some shared molecular biological pathogenesis,and they might be controlled by some common pleiotropic genes.Based on the existence of pleiotropic genes,pleiotropy-informed conditional false discovery rate(PCFDR)method can greatly increase the disco,very rate of trait-associated single nucleotide polymorphisms(SNP)as well as common SNPs for two highly associated diseases.We applied PCFDR method on OP’s main phenotype-lumbar spine bone mineral density(LS BMD)and CAD’s G’WAS data to find novel variants for OP and pleiotropic variants for both OP and CAD,aiming to apply more theoretical basis for the exploration of the disease’s pathogenesis.[Methods]We applied PCFDR method on the GWAS data of OP’s main study phenotype-LS BMD and CAD to perform a bivariate analysis.Conditional false discovery rate(cFDR)<0.05 and conjunction conditional false discovery rate(ccFDR)<0.05 were used as the significance thresholds.[Results]1.In the quantile-quantile plot(QQ plot),strong enrichment was observed for LS BMD-associated SNPs across different levels of association with CAD,and vice versa for CAD conditioned on LS BMD.2.Totally we identified 41 OP-associated SNPs(including 21 novel ones).Four genes(MEPE,CCDC170,SFRP4 and SOST)corresponding to OP-associated SNPs were partially validated in the gene expression validation analysis(P<0.05).OP-associated genes were enriched in a number of pathways that relating to bone metabolism,including Wnt signaling pathway,osteoclast differentiation pathway,estrogen metabolism pathway and bone absorption regulation pathway(P<0.05).These genes and proteins encoded by them participate in the pathogenesis of OP by inhibiting PPARγ,monitoring protein secretion and transportation in Wnt signaling pathway,regulating estrogen’s function and OPG/RANK/RANKL axis.3.We identified 7 pleiotropic SNPs associated with both OP and CAD.Genes corresponding to these pleiotropic SNPs can regulate insulin resistance and estrogen function,monitoring the secretion of brain-derived neurotrophic factor,and therefore participate in the common pathogenesis of OP and CAD through ERK,Ras/MAPK,PPARy and RANKL signaling pathways.[Conclusion]1.We identified 21 novel OP-associated variants that were not reported before.Our findings applied more theoretical content for the pathogenesis of OP.2.For the first time in the world we identified 7 pleiotropic SNPs for both OP and CAD.Our study provided strong theoretical foundation for the shared genetic basis underlying OP and CAD.3.Validated the efficiency and reliability of PCFDR method on identifying novel variants as well as pleiotropic variants for complex diseases in GWAS.4.Our findings provided theoretical basis for further functional experiments as well as the precise disease treatment and prevention.