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BACKGROUND: 15% of atopic dermatitis liability-scale heritability could be attributed to 31 susceptibility loci identified by genome-wide association studies, with only three of them (IL13, IL6R, and FLG) resolved to protein-coding variants.
OBJECTIVE: We examined whether a significant portion of unexplained atopic dermatitis heritability is further explained by low-frequency and rare variants in 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 controls, combined with whole transcriptome data on lesional, non-lesional and healthy skin samples of 27 patients and 38 controls.
RESULTS: Additional 12.56% (s.e. 0.74%) of atopic dermatitis 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 atopic dermatitis are further enriched in five genes (IL4R, IL13, JAK1, JAK2, TYK2) of the IL13 pathway, all of which are targets for novel systemic atopic dermatitis therapeutics. Multiomics-based network and RNA-Sequencing analysis revealed DOK2 as a central hub interacting, among others, with CD200R1, IL6R and STAT3. Multi-tissue gene expression profile analysis for 53 tissue types from GTEx 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 atopic dermatitis acting independently of common variants. Further extensive functional studies are required to detect all potential causal variants and to specify the contribution of novel susceptibility genes DOK2 and CD200R1 to overall disease susceptibility.