Triangulating molecular evidence to prioritise candidate causal genes at established atopic dermatitis loci
File(s)
Accepted version
OA Location
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.
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
2021-04-24
Date Acceptance
2021-03-25
Citation
Journal of Investigative Surgery, 2021
ISSN
0894-1939
Publisher
Taylor and Francis
Journal / Book Title
Journal of Investigative Surgery
Copyright Statement
© 2021 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. Under a Creative Commons license
License URL
Identifier
https://www.sciencedirect.com/science/article/pii/S0022202X2101160X?via%3Dihub
Subjects
eQTLGen Consortium
BIOS Consortium
GoDMC
Publication Status
Published online
Date Publish Online
2021-04-24