Beyond genome-wide association studies: Investigating the role of noncoding regulatory elements in primary sclerosing cholangitis.

ABSTRACT:

Background

Genome-wide association studies (GWAS) have identified 30 risk loci for primary sclerosing cholangitis (PSC). Variants within these loci are found predominantly in noncoding regions of DNA making their mechanisms of conferring risk hard to define. Epigenomic studies have shown noncoding variants broadly impact regulatory element activity. The possible association of noncoding PSC variants with regulatory element activity has not been studied. We aimed to (1) determine if the noncoding risk variants in PSC impact regulatory element function and (2) if so, assess the role these regulatory elements have in explaining the genetic risk for PSC.

Methods

Available epigenomic datasets were integrated to build a comprehensive atlas of cell type-specific regulatory elements, emphasizing PSC-relevant cell types. RNA-seq and ATAC-seq were performed on peripheral CD4+ T cells from 10 PSC patients and 11 healthy controls. Computational techniques were used to (1) study the enrichment of PSC-risk variants within regulatory elements, (2) correlate risk genotype with differences in regulatory element activity, and (3) identify regulatory elements differentially active and genes differentially expressed between PSC patients and controls.

Results

Noncoding PSC-risk variants are strongly enriched within immune-specific enhancers, particularly ones involved in T-cell response to antigenic stimulation. In total, 250 genes and >10,000 regulatory elements were identified that are differentially active between patients and controls.

Conclusions

Mechanistic effects are proposed for variants at 6 PSC-risk loci where genotype was linked with differential T-cell regulatory element activity. Regulatory elements are shown to play a key role in PSC pathophysiology.

SUBMITTER: Pratt HE 

PROVIDER: S-EPMC10531193 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature