303 Allele specific accessibility analysis to decipher molecular mechanism of psoriasis-associated loci

Abstract

Genome-wide association studies for psoriasis have identified >65 susceptibility regions, and our previous work has revealed these genetic signals overlap significantly with active enhancers in T-cells. To better understand the molecular mechanisms underlying the regulatory roles of these genetic signals, we conducted ATAC-seq to profile the chromatin accessibility patterns of resting and 24h CD3/CD28-activated T-cell subsets from >100 individuals. By tallying ATAC-seq read counts as a function of allelic variation, we assessed allele specific accessibility (ASA) for genetic variants mapping within +/- 100 kb of the 95% credible set of causal variants for the psoriasis-associated loci. By considering the directionality of the accessibility of the allele and information from multiple samples, we identified >700 sites with heterozygous genotypes and mapping to accessible chromatin in the ATAC-seq experiments. Genome-wide, we found stronger ASA in open chromatin regions depending on their proximity to psoriasis-associated signals. We further identified at least 9 psoriasis-associated loci encompassing markers exhibiting significant (FDR<=10%) ASA, including IL28RAand ZNF365, both of which manifested ASA in activated but not resting T-cells. By jointly leveraging sequence variation and chromatin accessibility information, our results provide novel insights to the molecular mechanisms of psoriasis-associated genetic variation. Ongoing sample size expansion and GWAS genotyping will add to the catalog of psoriasis-associated variants manifesting context-dependent ASA in T-cells, generating new hypotheses for functional and mechanistic studies.