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. 2019 Oct;20(4):3202-3214.
doi: 10.3892/mmr.2019.10570. Epub 2019 Aug 7.

PPWD1 is associated with the occurrence of postmenopausal osteoporosis as determined by weighted gene co‑expression network analysis

Guo-Feng Qian  1 , Lu-Shun Yuan  2 , Min Chen  1 , Dan Ye  1 , Guo-Ping Chen  1 , Zhe Zhang  1 , Cheng-Jiang Li  1 , Vijith Vijayan  3 , Yu Xiao  2
Affiliations

PPWD1 is associated with the occurrence of postmenopausal osteoporosis as determined by weighted gene co‑expression network analysis

Guo-Feng Qian et al. Mol Med Rep. 2019 Oct.

Abstract

Postmenopausal osteoporosis (PMO) is the most common type of primary osteoporosis (OP), a systemic skeletal disease. Although many factors have been revealed to contribute to the occurrence of PMO, specific biomarkers for the early diagnosis and therapy of PMO are not available. In the present study, a weighted gene co‑expression network analysis (WGCNA) was performed to screen gene modules associated with menopausal status. The turquoise module was verified as the clinically significant module, and 12 genes (NUP133, PSMD12, PPWD1, RBM8A, CRNKL1, PPP2R5C, RBM22, PIK3CB, SKIV2L2, PAPOLA, SRSF1 and COPS2) were identified as 'real' hub genes in both the protein‑protein interaction (PPI) network and co‑expression network. Furthermore, gene expression analysis by microarray in blood monocytes from pre‑ and post‑menopausal women revealed an increase in the expression of these hub genes in postmenopausal women. However, only the expression of peptidylprolyl isomerase domain and WD repeat containing 1 (PPWD1) was correlated with bone mineral density (BMD) in postmenopausal women. In the validation set, a similar expression pattern of PPWD1 was revealed. Functional enrichment analysis revealed that the fatty acid metabolism pathway was significantly abundant in the samples that exhibited a higher expression of PPWD1. Collectively, PPWD1 is indicated as a potential diagnostic biomarker for the occurrence of PMO.

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Figures

Figure 1.
Figure 1.
Sample clustering to detect outliers (GSE56815). (A) Cluster dendrogram. (B) Sample dendrogram and trait indicator. The color intensity was proportional to menopausal status and BMD level. BMD, bone mineral density.
Figure 2.
Figure 2.
Determination of soft-thresholding power in the WGCNA. (A) Analysis of the scale-free fit index for various soft-thresholding powers (β). (B) Analysis of the mean connectivity for various soft-thresholding powers. (C) Histogram of the connectivity distribution when β=8. (D) Verification of the scale-free topology when β=8. WGCNA, weighted gene co-expression network analysis.
Figure 3.
Figure 3.
Identification of modules associated with phenotypes. (A) Dendrogram of all differentially expressed genes clustered, based on a dissimilarity measure (1-TOM). (B) Heatmap of the correlation between module eigengenes and different phenotypes (menopausal status and BMD). (C) Distribution of average gene significance and errors in the modules associated with menopausal status. BMD, bone mineral density.
Figure 4.
Figure 4.
Hub gene detection. (A) Scatter plot of module eigengenes in the turquoise module. (B) The Venn diagram of co-expression hub genes and the PPI network hub genes. (C) Heatmap of the real hub genes. PPI, protein-protein interaction.
Figure 5.
Figure 5.
(A-F) Hub gene validation using the training set. (A) COPS2 (B) CRNKL1 (C) NUP133 (D) PAPOLA (E) PIK3CB (F) PPP2R5C. (G-L) Hub gene validation using the training set. (G) PPWD1 (H) PSMD12 (I) RBM8A (J) RBM22 (K) SKIV2L2 and (L) SRSF1. *P<0.05, **P<0.01, ***P<0.001. low, low BMD, high, high BMD, pre, premenopausal status, post, postmenopausal status; BMD, bone mineral density; PPWD1, peptidylprolyl isomerase domain and WD repeat containing 1.
Figure 5.
Figure 5.
(A-F) Hub gene validation using the training set. (A) COPS2 (B) CRNKL1 (C) NUP133 (D) PAPOLA (E) PIK3CB (F) PPP2R5C. (G-L) Hub gene validation using the training set. (G) PPWD1 (H) PSMD12 (I) RBM8A (J) RBM22 (K) SKIV2L2 and (L) SRSF1. *P<0.05, **P<0.01, ***P<0.001. low, low BMD, high, high BMD, pre, premenopausal status, post, postmenopausal status; BMD, bone mineral density; PPWD1, peptidylprolyl isomerase domain and WD repeat containing 1.
Figure 5.
Figure 5.
(A-F) Hub gene validation using the training set. (A) COPS2 (B) CRNKL1 (C) NUP133 (D) PAPOLA (E) PIK3CB (F) PPP2R5C. (G-L) Hub gene validation using the training set. (G) PPWD1 (H) PSMD12 (I) RBM8A (J) RBM22 (K) SKIV2L2 and (L) SRSF1. *P<0.05, **P<0.01, ***P<0.001. low, low BMD, high, high BMD, pre, premenopausal status, post, postmenopausal status; BMD, bone mineral density; PPWD1, peptidylprolyl isomerase domain and WD repeat containing 1.
Figure 5.
Figure 5.
(A-F) Hub gene validation using the training set. (A) COPS2 (B) CRNKL1 (C) NUP133 (D) PAPOLA (E) PIK3CB (F) PPP2R5C. (G-L) Hub gene validation using the training set. (G) PPWD1 (H) PSMD12 (I) RBM8A (J) RBM22 (K) SKIV2L2 and (L) SRSF1. *P<0.05, **P<0.01, ***P<0.001. low, low BMD, high, high BMD, pre, premenopausal status, post, postmenopausal status; BMD, bone mineral density; PPWD1, peptidylprolyl isomerase domain and WD repeat containing 1.
Figure 6.
Figure 6.
Hub gene validation using the validation set (GSE2208). (A) RBM22 (B) RBM8A (C) SKIV2L2 (D) PPWD1 (E) PSMD12 (F) PIK3CB (G) PAPOLA (H) CRKNL1 (I) COPS2 and (J) SRSF1. *P<0.05 and **P<0.01. PPWD1, peptidylprolyl isomerase domain and WD repeat containing 1; BMD, bone mineral density; ns, not significant.
Figure 6.
Figure 6.
Hub gene validation using the validation set (GSE2208). (A) RBM22 (B) RBM8A (C) SKIV2L2 (D) PPWD1 (E) PSMD12 (F) PIK3CB (G) PAPOLA (H) CRKNL1 (I) COPS2 and (J) SRSF1. *P<0.05 and **P<0.01. PPWD1, peptidylprolyl isomerase domain and WD repeat containing 1; BMD, bone mineral density; ns, not significant.
Figure 7.
Figure 7.
Bioinformatics analysis of genes in turquoise module. (A) GO analysis and (B) KEGG pathway analysis. GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.
Figure 7.
Figure 7.
Bioinformatics analysis of genes in turquoise module. (A) GO analysis and (B) KEGG pathway analysis. GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.
Figure 8.
Figure 8.
GSEA. (A and B) Gene sets related to BMD. (C) Gene sets related to menopausal status. (D) Gene sets related to PPWD1 expression. GSEA, gene set enrichment analysis; BMD, bone mineral density; PPWD1, peptidylprolyl isomerase domain and WD repeat containing 1.
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