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. 2016 Dec 5:8:131.
doi: 10.1186/s13148-016-0297-z. eCollection 2016.

Epigenome-wide association data implicates DNA methylation-mediated genetic risk in psoriasis

Fusheng Zhou #  1   2   3 , Changbing Shen #  1   4   5   6 , Jingkai Xu #  1   2   3 , Jing Gao  7 , Xiaodong Zheng  1   2   3 , Randy Ko  8 , Jinfa Dou  1   2   3 , Yuyan Cheng  1   2   3 , Caihong Zhu  1   2   3 , Shuangjun Xu  1   2   3 , Xianfa Tang  1   2   3 , Xianbo Zuo  1   2   3 , Xianyong Yin  9 , Yong Cui  10 , Liangdan Sun  1   2   3 , Lam C Tsoi  11   12   13 , Yi-Hsiang Hsu  4   5   6 , Sen Yang  1   2   3 , Xuejun Zhang  1   2   3   7
Affiliations

Epigenome-wide association data implicates DNA methylation-mediated genetic risk in psoriasis

Fusheng Zhou et al. Clin Epigenetics. .

Abstract

Background: Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation and altered keratinocyte differentiation and inflammation and is caused by the interplay of genetic and environmental factors. Previous studies have revealed that DNA methylation (DNAm) and genetic makers are closely associated with psoriasis, and strong evidences have shown that DNAm can be controlled by genetic factors, which attracted us to evaluate the relationship among DNAm, genetic makers, and disease status.

Methods: We utilized the genome-wide methylation data of psoriatic skin (PP, N = 114) and unaffected control skin (NN, N = 62) tissue samples in our previous study, and we performed whole-genome genotyping with peripheral blood of the same samples to evaluate the underlying genetic effect on skin DNA methylation. Causal inference test (CIT) was used to assess whether DNAm regulate genetic variation and gain a better understanding of the epigenetic basis of psoriasis susceptibility.

Results: We identified 129 SNP-CpG pairs achieving the significant association threshold, which constituted 28 unique methylation quantitative trait loci (MethQTL) and 34 unique CpGs. There are 18 SNPs were associated with psoriasis at a Bonferoni-corrected P < 0.05, and these 18 SNPs formed 93 SNP-CpG pairs with 17 unique CpG sites. We found that 11 of 93 SNP-CpG pairs, composed of 5 unique SNPs and 3 CpG sites, presented a methylation-mediated relationship between SNPs and psoriasis. The 3 CpG sites were located on the body of C1orf106, the TSS1500 promoter region of DMBX1 and the body of SIK3.

Conclusions: This study revealed that DNAm of some genes can be controlled by genetic factors and also mediate risk variation for psoriasis in Chinese Han population and provided novel molecular insights into the pathogenesis of psoriasis.

Keywords: DNA methylation; Epigenome; Genetic risk; Psoriasis.

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Figures

Fig. 1
Fig. 1
DNA methylation pattern of MethQTL CpG sites. a The distributions of CpG sites based on their locations in RefSeq genes. “Genome” represents all of the mapped methylation sites (N = 345,753). “MethQTL” represents MethQTL CpG sites (N = 31) are controlled by genetic makers. b Standard variation across the whole genome in terms of the gene context
Fig. 2
Fig. 2
Association and functional annotation of MethQTL SNPs that located in MHC region. a Scatter plot indicates association between MethQTL SNPs and psoriasis. The most significant disease-associated signal rs130079 and the most significant CIT-tested SNP rs13203895 are highlighted in vertical lines. b The first part of Fig. 2b reveals Refseq genes in the interrogated region. The next three lines show transcriptional activity, H3K4me3 and H3K27ac data across several cell lines from Encode project (GM12878, H1-hESC, HSMM, HUVEC, K562, NHEK and NHLF). The last five lines show evolutionary conservation in mammals, including in mouse, sheep, pig, horse, and dog
Fig. 3
Fig. 3
Genotype-dependent CpGs potentially mediate genetic risk for psoriasis and the relationship among cg04087571, rs10484554, and psoriasis. a Association between cg04087571 and disease status. b Association between cg04087571 and rs10484554. Red horizontal bars represent average DNA methylation levels. c Percentage of cases for each rs10484554 genotype. d The coefficient (β) represents the dependence of psoriasis phenotype (P) on genotype (G) with or without adjustment for DNA methylation level of cg04087571 (M). The bars represent the 95% confidence interval for the coefficient. e, f Examples of DMSs potentially mediate genetic risk for psoriasis. Density plots of methylation levels by genotype for two SNP-CpG pairs. Plot lines were colored by different genotypes
Fig. 4
Fig. 4
Identification of epigenetically mediated genetic risk factors for psoriasis. a Possible relationship between causal factor (G), a possible mediator (M), and an outcome (Y). Top, the methylation-mediated relationship, in which genotype (G) acts on phenotype (Y) through methylation (M); middle, the consequential methylation model, in which DNA methylation (M) changes are the consequence of phenotype (Y); bottom, the independent model, in which the genotype (G) acts on DNA methylation (M) and phenotype (Y) independently. b The four components of the CIT. c Flow diagram and results for identifying epigenetically mediated genetic risk for psoriasis
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