期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 141, 期 11, 页码 2620-2629出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2021.03.027
关键词
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类别
资金
- Springboard award [SBF003y1094]
- Academy of Sciences
- Wellcome Trust
- UK Government Department of Business, Energy and Industrial Strategy
- British Heart Foundation
- UK Medical Research Council [MC_UU_00011/4]
- Medical Research Council
- European Union, Chronic Disease Research Foundation
- Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust
- King's College London (United Kingdom) [10074]
- UK Research and Innovation [MR/S003886/1]
The study prioritized candidate causal genes for atopic dermatitis using bioinformatics analysis, finding enrichment of genes with immune regulatory function and epidermal barrier formation among the top-prioritized genes. At eight loci, a single candidate gene was prioritized, while less familiar candidates were prioritized at 6 of the 25 loci, presenting potential targets for drug discovery. This analysis supports previously implicated genes at several atopic dermatitis GWAS loci and suggests plausible additional candidates at others.
GWASs for atopic dermatitis have identified 25 reproducible loci. We attempt to prioritize the candidate causal genes at these loci using extensive molecular resources compiled into a bioinformatics pipeline. We identified a list of 103 molecular resources for atopic dermatitis etiology, including expression, protein, and DNA methylation quantitative trait loci datasets in the skin or immune-relevant tissues, which were tested for overlap with GWAS signals. This was combined with functional annotation using regulatory variant prediction and features such as promoter-enhancer interactions, expression studies, and variant fine mapping. For each gene at each locus, we condensed the evidence into a prioritization score. Across the investigated loci, we detected significant enrichment of genes with adaptive immune regulatory function and epidermal barrier formation among the top-prioritized genes. At eight loci, we were able to prioritize a single candidate gene (IL6R, ADO, PRR5L, IL7R, ETS1, INPP5D, MDM1, TRAF3). In addition, at 6 of the 25 loci, our analysis prioritizes less familiar candidates (SLC22A5, IL2RA, MDM1, DEXI, ADO, STMN3). Our analysis provides support for previously implicated genes at several atopic dermatitis GWAS loci as well as evidence for plausible additional candidates at others, which may represent potential targets for drug discovery.
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