Multi-omic insights from a multi-ancestry genome-wide meta-analysis of ankylosing spondylitis reveal novel pathways of disease susceptibility.

We report the largest genome-wide association study meta-analysis in ankylosing spondylitis (AS) to date (25,645 cases, 71,224 controls), identifying 27 novel loci and 86 independent genetic associations. Variations in (non-secretor status) and (blood group A) increase AS risk, with Mendelian randomisation (MR) linking non-secretor status to increased AS risk from reduced gut carriage of . Associations with three telomerase maintenance genes (, ), and MR analysis, suggest increased telomere length causally increases AS susceptibility. Fine-mapping prioritised likely causal variants at multiple loci. Transcriptome- and proteome-wide association studies implicated 644 genes, highlighting immune-related pathways. Lower genetically-determined IL-6 and IL-12, and similar IL-23, levels were found in AS cases, offering a genetic explanation for the failure of IL-6, IL-12, and IL-23 inhibition in AS treatment. Finally, multi-omic analyses showed chromosome 2p15 association acts via reduced expression. These findings deepen understanding of AS pathogenesis, highlighting new pathways and therapeutic opportunities.