Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis
Brown AC., Cohen CJ., Mielczarek O., Migliorini G., Costantino F., Allcock A., Davidson C., Elliott KS., Fang H., Lledó Lara A., Martin AC., Osgood JA., Sanniti A., Scozzafava G., Vecellio M., Zhang P., Black MH., Li S., Truong D., Molineros J., Howe T., Wordsworth BP., Bowness P., Knight JC.
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.