Original Article
Genetics/Genetic Disease
Triangulating Molecular Evidence to Prioritize Candidate Causal Genes at Established Atopic Dermatitis Loci

https://doi.org/10.1016/j.jid.2021.03.027Get rights and content
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open access

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.

Abbreviations

AD
atopic dermatitis
bp
base pair
eQTL
expression quantitative trait locus
GTEx
Genotype-Tissue Expression
QTL
quantitative trait locus
STAT
signal transducer and activator of transcription
Th
T helper
TWAS
transcriptome-wide association study

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See related commentary on pg 2561