Integrative Functional Genomics Points to Natural Killer Cells as Key Drivers in Pathogenesis of Ankylosing Spondylitis

Multiple lines of evidence indicate that ankylosing spondylitis (AS) is a lymphocyte-driven disease. However, which lymphocyte populations are critical in AS pathogenesis is not known. AS is a highly heritable disease, with estimates of the genetic contribution to AS ranging from 69-90%. Genome wide associations studies (GWAS) have identified >100 loci associated with AS, with the vast majority of likely causal variants being non-coding.

Here we integrate GWAS data with epigenomic and transcriptomic datasets in human lymphocytes to identify key cell subsets mediating genetic susceptibility to AS. We use public ATAC-seq on sorted peripheral immune cell subsets of healthy subjects, single-cell RNA-seq on lymphocytes of AS patients and healthy controls, and low-input RNA-seq on 7 sorted lymphocyte populations of healthy subjects. To link cell type-specific open chromatin regions or gene expression with GWAS we use 3 methods: Linkage Disequilibrium Score-regression in Specifically Expressed Genes (LDSC-seg), single-cell disease-relevance score (scDRS) and SNPsea. We validated that our methods could identify T-cells as the main drivers of Rheumatoid Arthritis.

We discovered that open chromatin regions and gene expression that is specific to Natural Killer (NK) cells compared to other immune cell-types, are enriched in genetic risk loci for AS. These results are consistent between two independent GWAS, and using 3 independent methods in 3 independent functional genomics datasets. Our data points to putative causal genes for AS that may play important roles in NK cell biology. Unexpectedly, these results suggest that NK cells may be key mediators of the genetic susceptibility to AS.