Introduction/Aim: Ankylosing spondylitis (AS) is a highly heritable inflammatory arthritis common in both Asian and European populations. Thus far genes identified include the HLA-B*27 allele, and 13 non-MHC loci identified in European populations. In this study we aimed to better characterize the genetic architecture of AS and to fine-map known susceptibility loci.
Materials and Methods: We successfully genotyped 129,030 polymorphic SNPs in 10,624 AS affected and 15,174 healthy individuals of European and Asian descent using the Illumina Immunochip microarray, which designed for immunogenetic studies.
Results: In this study we identified 16 new AS risk loci reaching genome-wide significance (P< 5x10-8), bringing the number of known non-MHC loci to 27. We found multiple independent association signals in 8 of these loci, caused by both common and low frequency variants, suggesting that multiple genetic variants within a gene can affect disease susceptibility. A second MHC association with the classical HLA-A*0201 was observed in both HLA-B*27 positive and negative disease (OR=1.2; P= 4.5 × 10-9). European and Asian specific signals were observed in IL23R and PTGER4.
Discussion: This study has replicated all attempted genome-wide significant loci reported in European populations and identified 16 novel susceptibility loci. Identified loci implicate microbial sensing (NOS2, NKX2-3, SH2B3 and ICOSLG), intracellular antigenic peptide handling (ERAP1, ERAP2, LNPEP and NPEPPS) and CD8+ T cells (EOMES and IL7R) pathways as important in AS etiology as well as increase the number of susceptibility genes in the TH17 pathway (TYK2 and IL6R).
Conclusion: This increased characterization of the genetic architecture of AS aids greatly in explaining the currently poorly understood high observed heritability and familiality in AS. This data also guides functional studies towards uncovering how these genes cause disease and in the development of new therapeutics.