Abstract
Integration of multiple profiling data and construction of functional gene networks may provide additional insights into the molecular mechanisms of complex diseases. Osteoporosis is a worldwide public health problem, but the complex gene-gene interactions, post-transcriptional modifications and regulation of functional networks are still unclear. To gain a comprehensive understanding of osteoporosis etiology, transcriptome gene expression microarray, epigenomic miRNA microarray and methylome sequencing were performed simultaneously in 5 high hip BMD (Bone Mineral Density) subjects and 5 low hip BMD subjects. SPIA (Signaling Pathway Impact Analysis) and PCST (Prize Collecting Steiner Tree) algorithm were used to perform pathway-enrichment analysis and construct the interaction networks. Through integrating the transcriptomic and epigenomic data, firstly we identified 3 genes (FAM50A, ZNF473 and TMEM55B) and one miRNA (hsa-mir-4291) which showed the consistent association evidence from both gene expression and methylation data; secondly in network analysis we identified an interaction network module with 12 genes and 11 miRNAs including AKT1, STAT3, STAT5A, FLT3, hsa-mir-141 and hsa-mir-34a which have been associated with BMD in previous studies. This module revealed the crosstalk among miRNAs, mRNAs and DNA methylation and showed four potential regulatory patterns of gene expression to influence the BMD status. In conclusion, the integration of multiple layers of omics can yield in-depth results than analysis of individual omics data respectively. Integrative analysis from transcriptomics and epigenomic data improves our ability to identify causal genetic factors, and more importantly uncover functional regulation pattern of multi-omics for osteoporosis etiology.
Highlights
Osteoporosis is a worldwide public health problem characterized by low bone mineral density (BMD) and a high risk of osteoporotic fracture [1]
It was shown that rs3747486 and rs3812999 in RNF40 were associated with femoral neck (FN) BMD in GEFOS2
Gene ALDOA was found to be associated with FN BMD in GEFOS2, with P = 2.0E-2
Summary
Osteoporosis is a worldwide public health problem characterized by low bone mineral density (BMD) and a high risk of osteoporotic fracture [1]. Recent advances in high-throughput technologies enable interrogation of various biological components on a genome wide scale (i.e., genomics, transcriptomics, epigenomics and proteomics), which have uncovered a number of risk factors/genes for human complex diseases and osteoporosis [3, 4] These implicated genes explain no more than 10% of BMD variation in any individual human population [5]. While individual omics studies (genome/transcriptome/epigenome/proteome) are useful in identifying association of molecules with disease risk, they fall short of illuminating the underlying functional mechanisms It is usually not feasible for uni-omics studies to provide a comprehensive view of the genetic factors and their functions in the form of complex function/regulatory networks for the etiology of osteoporosis [7]. On the contrary, integrating multi-omics data may yield most thorough information to most powerfully and comprehensively identify molecular and genomic factors/mechanisms underlying the pathogenesis of osteoporosis, by identifying and characterizing those individual molecules as well as their involved complex regulation networks embedded in and across multi-level and multi-facet-omics data [8]
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