Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression

Abstract

Background: Fifteen percent of atopic dermatitis (AD) liability-scale heritability could be attributed to 31 susceptibility loci identified by using genome-wide association studies, with only 3 of them (IL13, IL-6 receptor [IL6R], and filaggrin [FLG]) resolved to protein-coding variants. Objective: We examined whether a significant portion of unexplained AD heritability is further explained by low-frequency and rare variants in the gene-coding sequence. Methods: We evaluated common, low-frequency, and rare protein-coding variants using exome chip and replication genotype data of 15,574 patients and 377,839 control subjects combined with whole-transcriptome data on lesional, nonlesional, and healthy skin samples of 27 patients and 38 control subjects. Results: An additional 12.56% (SE, 0.74%) of AD heritability is explained by rare protein-coding variation. We identified docking protein 2 (DOK2) and CD200 receptor 1 (CD200R1) as novel genome-wide significant susceptibility genes. Rare coding variants associated with AD are further enriched in 5 genes (IL-4 receptor [IL4R], IL13, Janus kinase 1 [JAK1], JAK2, and tyrosine kinase 2 [TYK2]) of the IL13 pathway, all of which are targets for novel systemic AD therapeutics. Multiomics-based network and RNA sequencing analysis revealed DOK2 as a central hub interacting with, among others, CD200R1, IL6R, and signal transducer and activator of transcription 3 (STAT3). Multitissue gene expression profile analysis for 53 tissue types from the Genotype-Tissue Expression project showed that disease-associated protein-coding variants exert their greatest effect in skin tissues. Conclusion: Our discoveries highlight a major role of rare coding variants in AD acting independently of common variants. Further extensive functional studies are required to detect all potential causal variants and to specify the contribution of the novel susceptibility genes DOK2 and CD200R1 to overall disease susceptibility.

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

“…Another multi-omic approach included a highly diverse patient collective to investigate low-frequency and rare-coding variants associated with AD to improve the understanding of disease heredity. Through this in-depth view, they found a new and potentially therapeutic target comprising the surface receptor CD200R1 and its associated adaptor protein DOK2 [49].…”

What Have We Learned from GWAS for Atopic Dermatitis?

“…An extension to GWAS, focusing on protein-coding variants, used exome genotype and skin transcriptome data (Mucha et al, 2019). This study identified an additional 12% of AD heritability explained by rare protein-coding variation in genes including IL4R, IL13, JAK1, JAK2 and TYK2, as well as novel candidate genes DOK2 and CD200R1.…”

“…GWAS findings to date account for <20% of AD heritability (Paternoster et al, 2015) and even with the additional risk attributed to protein-coding variants, ~70% of heritability remains to be explained (Mucha et al, 2019). Considerable further work is therefore needed to fully understand individual risk.…”

“…It is known that drugs targeting molecules or pathways informed by human genetic studies have above-average chance of clinical success (Kamb et al, 2013). The genome-wide approach (described above) to define variants in protein-coding regions identified multiple proteins in the IL-13 pathway, and all have been successfully targeted in novel AD treatments (Mucha et al, 2019). Translational genomics, drug development and personalised medicine will progress in tandem (Figure 2) (Dugger et al, 2018, Zeggini et al, 2019 and dermatological research is poised to be at the forefront of these exciting developments in clinical care.…”

Current Developments of Clinical Sequencing and the Clinical Utility of Polygenic Risk Scores in Inflammatory Diseases

“…Current estimates of heritability explained by common AD susceptibility variants (minor allele frequency MAF≥1%) amount to 14.91%. An additional 12.56% of heritability are estimated to be attributable to rare protein-coding variants (MAF<1%) ( 21 ).…”