Genomic And Proteomic Analyses For The Pathogenesis Of Osteoporosis

Osteoporosis,one of the most common public health threats in modern society,is a chronic skeletal disorder featuring whole-body loss of bone mineral density(BMD)and micro-architectural deterioration of bone tissue.In order to identify risk genes and proteins of osteoporosis,two studies have been carried out in this thesis.Study 1:To further exploit the potential value of Genome-wide association(GWA)study,this study combined the summary statistic P values of SNPs across individual genes to represent the association of the gene with BMD by using the Gene-based method.The two GWA meta-analyses(GEFOS2 and GEFOS-seq)published by the Genetic Factors for Osteoporosis(GEFOS)studies were used for the Gene-based analysis.Since the two consecutive GEFOS studies have many overlapping samples,this study estimated the correlation of the P values of the same SNPs/genes to evaluate the consistency between the two GEFOS studies.Compared to the SNP-based analysis,the Gene-based strategy identified additional significant BMD-associated genes(GEFOS2:51 vs.42,GEFOS-seq:45 vs.5)and increased their mutual replication between the two GEFOS datasets(47 vs.13).This study found 3 novel BVMD-associated genes including UBTF(PGEFOS2=1.21E-09,PGEFOS-seq=1.33E-07,QmRNA=2.09E-02),AAAS(PEFOS2=1.81E-10,P GEFOS-seq =2.83E-07,QmRNA=4.05E-02)and cllorf58(PGEFOS-seq=4.96E-07,QmRNA=4.19E-03).The correlation analysis presented a moderately high between—study consistency of potential BMD-associated variants.Study 2:This study performed a cytosolic sub-proteome profiling analysis in peripheral blood monocytes(PBMs)to identify differentially expressed proteins(DEPs)that are associated with BMD and risk of osteoporosis.The study sample included 30 Caucasian men with extremely high BMD and 29 with extremely low BMD,and liquid chromatography(LC)?mass spectrometry(MS)was used to perform a comparative proteomics analysis.Of the total of 3,796 detected cytosolic proteins,we identified 16 significant(P<0.05)and an additional 22 suggestive(P<0.1)DEPs between samples with low vs.high hip BMDs.Thirteen of the genes for DEPs,including ALDOA(QMulti-omics=5.51E-03)?MYH14(QMulti-omics=2.57E-05)and RAP1B(QMulti-omics=4.93E-03),were associated with BMD in multiple-omics studies(proteomic,transcriptomic and genomic).Further bioinformatics analysis revealed the enrichment of DEPs in functional terms for monocyte proliferation,differentiation and migration.This study identified 3 novel BMD-associated genes by a Gene-based GWA method and 13 BMD-associated proteins by a cytosolic sub-proteome profiling analysis in peripheral blood monocytes(PBMs),which further revealed the genetic mechanism of osteoporosis.