Triangulating Molecular Evidence to Prioritize Candidate Causal Genes at Established Atopic Dermatitis Loci

Maria K Sobczyk,Tom G Richardson,Verena Zuber,Josine L Min,Tom R Gaunt,Lavinia Paternoster

doi:10.1016/j.jid.2021.03.027

Abstract

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.

Highlights

Defined by inflamed dry, hyperplastic eczematous skin and pruritus, atopic dermatitis (AD) is among the world’s top 50 common diseases, with prevalence in 2010 estimated at close to 230 million cases and increasing (Hay et al, 2014)
Identification of key tissues and cell types in AD GWAS loci To determine which tissues and cell types should be part of the pipeline, we tested for enrichment of expression at our GWAS loci across a wide range of tissues and cell types (53 tissues from Genotype-Tissue Expression [GTEx], version 7, and 79,249,533 cell types from the Gene Atlas, Immunological Genomics, and FANTOM CAGE [Functional Annotation of the Mouse/Mammalian Genome Cap Analysis of Gene Expression]) and determined that all immune cell, skin, spleen, and whole-blood datasets should be included (Supplementary Results)
Previous annotations of AD GWAS loci have been limited in their ability to identify likely causal genes (Paternoster et al, 2015)

Summary

Introduction

Hyperplastic eczematous skin and pruritus, atopic dermatitis (AD) is among the world’s top 50 common diseases, with prevalence in 2010 estimated at close to 230 million cases and increasing (Hay et al, 2014). AD is highly heritable, with estimates of up to 75% in twin studies (Elmose and Thomsen, 2015). The largest and most recent GWAS of AD undertaken by the EAGLE (EArly Genetics and Lifecourse Epidemiology) consortium in 2015 identified 25 loci associated with AD in individuals of European descent (Paternoster et al, 2015). Since the publication of the AD EAGLE GWAS, there has been an explosion of new datasets from many cell types and 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

Objectives

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Results

Conclusion