Whole-genome sequencing reveals rare and structural variants contributing to psoriasis and identifies CERCAM as a risk gene.
Sonehara K, Watanabe R, Matsumura Y et al.
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Psoriasis vulgaris (PsV) is an immune-mediated inflammatory skin disorder with complex genetic architecture. Most genome-wide association studies (GWASs) of PsV have been limited to analyzing common single-nucleotide variants in Europeans, lacking diversity in the variant spectrum and ancestral background. To investigate the contribution of rare variants (RVs) and structural variants (SVs), we perform a whole-genome sequencing study involving 1,415 PsV cases and 3,968 controls in Japanese. A GWAS signal at IFNLR1 is fine-mapped to a 3.3-kb deletion SV disrupting an epithelium-specific putative enhancer, which is validated by PacBio long-read sequencing. Gene-based RV analyses identify two susceptibility genes: IFIH1 (p = 9.8 × 10-6) and CERCAM (p = 4.1 × 10-7). Notably, IL36RN, a causative gene for generalized pustular psoriasis, a rare and lethal multi-systemic inflammatory disorder, is associated with common PsV (p = 1.2 × 10-4). Finally, Cercam knockout (Cercam-/-) in an imiquimod-induced psoriasis mouse model aggravates dermatitis with elevated T cell retention in the subepidermis. Our study elucidates the overlooked genetic basis of PsV.
1,415 Japanese ancestry cases, 3,968 Japanese ancestry controls
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