DNA methylation and gene expression changes in monozygotic twins discordant for psoriasis: identification of epigenetically dysregulated genes

Abstract

Monozygotic (MZ) twins do not show complete concordance for many complex diseases; for example, discordance rates for autoimmune diseases are 20%-80%. MZ discordance indicates a role for epigenetic or environmental factors in disease. We used MZ twins discordant for psoriasis to search for genome-wide differences in DNA methylation and gene expression in CD4(+) and CD8(+) cells using Illumina's HumanMethylation27 and HT-12 expression assays, respectively. Analysis of these data revealed no differentially methylated or expressed genes between co-twins when analyzed separately, although we observed a substantial amount of small differences. However, combined analysis of DNA methylation and gene expression identified genes where differences in DNA methylation between unaffected and affected twins were correlated with differences in gene expression. Several of the top-ranked genes according to significance of the correlation in CD4(+) cells are known to be associated with psoriasis. Further, gene ontology (GO) analysis revealed enrichment of biological processes associated with the immune response and clustering of genes in a biological pathway comprising cytokines and chemokines. These data suggest that DNA methylation is involved in an epigenetic dysregulation of biological pathways involved in the pathogenesis of psoriasis. This is the first study based on data from MZ twins discordant for psoriasis to detect epigenetic alterations that potentially contribute to development of the disease.

Figure 1. Volcano plots of cell-type specific differences in DNA methylation and gene expression.

(A) Differences in DNA methylation between CD4⁺ and CD8⁺ cells. Each point represents a CpG site, with mean β-value difference across 12 unaffected individuals along the x-axis and −log10 of a corrected P-value from a paired t-test along the y-axis. (B) Differences in gene expression between CD4⁺ and CD8⁺ cells. Each point represents a gene, with mean log2 fold change across 13 unaffected individuals along the x-axis and −log10 of a corrected P-value from a paired t-test along the y-axis. Dashed lines represent the FDR of 5%.

Figure 2. Volcano plots of differences in DNA methylation and gene expression in discordant MZ twins.

(A–B) Differences in DNA methylation in CD4⁺ (n = 17 pairs) and CD8⁺ cells (n = 13 pairs), respectively. Each point represents a gene, with mean co-twin β-value difference along the x-axis and −log10 of the uncorrected P-value from a paired t-test along the y-axis. (C–D) Differences in gene expression in CD4⁺ cells (n = 17 pairs) and CD8⁺ cells (n = 14 pairs), respectively. Each point represents a gene, with mean log2 fold change along the x-axis and log odds along the y-axis.

Figure 3. Scatter plots of differences in DNA methylation against the differences in gene expression of TNFSF11.

The plots show a correlation of DNA methylation differences and gene expression differences in MZ co-twins. Each point represents a twin pair, with the mean difference in DNA methylation β-value (of 2 CpG sites) along the x-axis, and log2 fold change along the y-axis. A correlation of 0.87 was calculated in CD4⁺ cells.