Triangulating molecular evidence to prioritize candidate causal genes at established atopic dermatitis loci

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

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

1 Citation (Scopus)
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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.
Original languageEnglish
Article numberS0022-202X(21)01160-XDOI
Pages (from-to)2620-2629
Number of pages10
JournalJournal of Investigative Dermatology
Volume141
Issue number11
Early online date23 Apr 2021
DOIs
Publication statusPublished - Nov 2021

Bibliographical note

Funding Information:
This work was supported by a Springboard award (SBF003∖1094) to LP; by the Academy of Sciences; by the Wellcome Trust; by the UK Government Department of Business, Energy and Industrial Strategy; and the British Heart Foundation . TRG acknowledges support from the UK Medical Research Council (MC_UU_00011/4). TGR is a UK Research and Innovation research fellow (MR/S003886/1). TwinsUK is funded by Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation , Zoe Global, and the National Institute for Health Research‒funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London (United Kingdom). Fine-mapping analysis used the UK Biobank genetic data resource as an linkage disequilibrium reference [application #10074]. This work was done in Bristol, United Kingdom.

Funding Information:
This work was supported by a Springboard award (SBF003?1094) to LP; by the Academy of Sciences; by the Wellcome Trust; by the UK Government Department of Business, Energy and Industrial Strategy; and the British Heart Foundation. TRG acknowledges support from the UK Medical Research Council (MC_UU_00011/4). TGR is a UK Research and Innovation research fellow (MR/S003886/1). TwinsUK is funded by Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation, Zoe Global, and the National Institute for Health Research?funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy's and St Thomas? NHS Foundation Trust in partnership with King's College London (United Kingdom). Fine-mapping analysis used the UK Biobank genetic data resource as an linkage disequilibrium reference [application #10074]. This work was done in Bristol, United Kingdom. Conceptualization: MKS, TRG, LP; Data Curation: MKS; Funding Acquisition: LP; Investigation: MKS; Methodology: MKS, TRG, LP; Resources: VZ, JLM, LP; Supervision: TRG, LP; Validation: TGR; Writing - Original Draft Preparation: MKS, TRG, LP; Writing - Review and Editing: MKS, TGR, VZ, JLM, TRG, LP

Funding Information:
TRG receives funding from GlaxoSmithKline and Biogen for unrelated research. The remaining authors state no conflict of interest.

Publisher Copyright:
© 2021 The Authors

Keywords

  • GWAS
  • genome-wide association study
  • eczema
  • atopic dermatitis
  • triangulation
  • eQTL

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