Whole-genome sequencing identifies risk genes for generalized pustular psoriasis

Summary: Abstract Body: Generalized pustular psoriasis (GPP) is a rare, chronic and potentially life-threatening systemic inflammation disorder characterized by widespread pustular rash. Earlier studies reported causative genes for GPP, but they relied mostly on the candidate gene approach with a limited sample size. A non-biased, thorough genome-wide investigation is warranted to capture the comprehensive genetic architecture of GPP. To this aim, we performed a high-coverage (median depth >29×) whole-genome sequencing (WGS) analysis on 121 Japanese patients with GPP recruited through a nationwide collaboration, comparing them with 1,412 common psoriasis cases (PsV) and 3,914 controls without a history of immune diseases. A genome-wide association study analyzing 6,910,328 SNPs identified common genetic variants (minor allele frequency >1%) associated with the GPP risk at the IL36RN and major histocompatibility complex (MHC) loci (Odds ratio [OR] = 5.9 and 4.1, P = 1.4×10-13 and 2.1×10-13, respectively). When comparing GPP and PsV, the IL36RN locus risk was GPP-specific (OR = 4.1, P = 2.3×10-8), while the MHC risk was comparable between the two diseases (P = 0.24). An HLA fine-mapping analysis showed that the strongest associated HLA variant was HLA-A*02:07:01 (P = 1.6×10-10), which was previously reported as a risk HLA variant of PsV in Japanese population. The well-known PsV risk as HLA variant HLA-C*06:02 was independently associated with the GPP risk (P = 0.0030 when conditioned on HLA-A*02:07:01). Finally, utilizing rare variants detected by WGS, we identified GPP risk genes, including IL36RN, in which protein-altering coding variants were significantly enriched in the cases. Our study provides a first comprehensive landscape of genetic determinants of GPP and evidence of the population-level contribution of IL36RN to GPP pathogenesis. Kyuto Sonehara¹, Yosuke Ogawa¹, Morihisa Saitoh², Yukinori Okada¹, Akimichi Morita³ 1. Graduate School of Medicine, the University of Tokyo, Tokyo, Japan. 2. Nippon Boehringer Ingelheim Co. Ltd, Tokyo, Japan. 3. Nagoya City University Graduate School of Medical Sciences, Aichi, Japan. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics