Triangulating molecular evidence to prioritize candidate causal genes at established atopic dermatitis loci
File(s)1-s2.0-S0022202X2101160X-main(1).pdf (622.75 KB)
Published version
Author(s)
Type
Journal Article
Abstract
Genome-wide association studies for atopic dermatitis (AD) have identified 25 reproducible loci. We attempt to prioritize candidate causal genes at these loci using extensive molecular resources compiled into a bioinformatics pipeline. We identified a list of 103 molecular resources for AD aetiology, including expression, protein and DNA methylation QTL datasets in 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 8 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 AD GWAS loci, as well as evidence for plausible additional candidates at others, which may represent potential targets for drug discovery.
Date Issued
2021-11-01
Date Acceptance
2021-03-25
Citation
Journal of Investigative Dermatology, 2021, 141 (11), pp.2620-2629
ISSN
0022-202X
Publisher
Elsevier
Start Page
2620
End Page
2629
Journal / Book Title
Journal of Investigative Dermatology
Volume
141
Issue
11
Copyright Statement
© 2021 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. Pre-proof version available open access under a CC-BY licence (https://creativecommons.org/licenses/by/4.0/)
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/33901562
PII: S0022-202X(21)01160-X
Subjects
eQTLGen Consortium, BIOS Consortium, GoDMC
1103 Clinical Sciences
1112 Oncology and Carcinogenesis
Dermatology & Venereal Diseases
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2021-04-24