Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis

Journal article

Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterized by enthesitis of the spine and sacroiliac joints. Genome-wide association studies (GWASs) have revealed more than 100 genetic associations whose functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We find that, while CD14+ monocytes and CD4+ and CD8+ T cells show disease-specific differences at the RNA level, epigenomic differences are only apparent upon multi-omics integration. The latter reveals enrichment at disease-associated loci in monocytes. We link putative functional SNPs to genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1, and show how disease-specific functional genomic data can be integrated with GWASs to enhance therapeutic target discovery. This study combines epigenetic and transcriptional analysis with GWASs to identify disease-relevant cell types and gene regulation of likely pathogenic relevance and prioritize drug targets.

Authors: Brown, AC; Cohen, CJ; Mielczarek, O; Migliorini, G; Costantino, F

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Cell Genomics
• Volume: 3
• Issue: 6
• Article number: 100306
• Publication date: 2023-04-24
• Acceptance date: 2023-03-27
• DOI: 10.1016/j.xgen.2023.100306
• EISSN: 2666-979X
• Language: English
• Keywords: genome-wide association study; gene regulation; functional genomics; epigenomics; spondyloarthritis; chromatin interactions; ankylosing spondylitis; target discovery; transcriptomics; FFR