Psoriasis Risk Variant Dynamically Affects TNFAIP3 Gene Expression in the Context of an Infectious Trigger: An Example of Fine Mapping

The vast majority of risk loci (over 90%) associated with autoimmune diseases are located in the noncoding regions of the genome and have not been fine-mapped down to individual causal variants. Prioritizing these causal variants is complicated by linkage disequilibrium and the unknown function of the noncoding genetic variation. In this study, we prioritized causal variants within 64 loci associated with psoriasis risk. We first employed the SUSIE method to estimate the conditional (a posteriori) causal probability of each candidate polymorphism within a given risk locus. We then narrowed down potential functional variants by colocalizing candidate SNPs with eQTLs that affected gene expression in immune cells. Specifically, we ran colocalization analysis with eQTL markers from 23 immune cell types and 48 human tissues from the Genotype-Tissue Expression (GTEx) Consortium. A careful selection of eQTL markers in immune cells related to pathogenesis enabled us to predict the molecular function of putative causal variants at two risk loci. These causal variants function dynamically in the activated states of two immune cell types and were absent in the GTEx human tissue eQTL marker sets. Finally, we cross-checked genomic sites for the inferred regulatory variants by comparing them with chromatin modifications associated with gene expression regulation. This paper presents a detailed analysis and discussion of a regulatory variant affecting TNFAIP3 gene expression in antigen-presenting monocytes activated by bacterial ligands. The dynamic role of the causal variant at the risk locus in response to bacterial ligands aligns with the well-known triggering effect of bacterial infection in the onset and exacerbation of psoriasis. Thus, our findings shed light on the molecular mechanisms underlying genetic–environmental interactions involved in the pathogenesis of psoriasis.