Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci

Abstract

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10(-800)), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 x 10(-19)) and 21q22 (rs2242944; P = 8.3 x 10(-20)), as well as in the genes ANTXR2 (rs4333130; P = 9.3 x 10(-8)) and IL1R2 (rs2310173; P = 4.8 x 10(-7)). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 x 10(-14)) and ERAP1 (rs27434; P = 5.3 x 10(-12)). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.

Figure 1

SNP association plots for ankylosing spondylitis–associated regions. Discovery cohort association significance is plotted against the left hand y axis as −log₁₀ (P-value). Genetic coordinates are as per NCBI dbSNP genome build 128 (October 2007). Filled circles, genotyped SNPs; open diamonds, imputed SNPs; color scale, LD; purple dotted line and right y axis, recombination rate (cM/Mb as per HapMap data). Positions of gene exons and ESTs are indicated below the x axis, with their direction of translation (gray arrows). (a) Chromosome 1p31 region. SNP association plot for a 295-kb region (67,325 kb to 67,620 kb) of chromosome 1. LD is in relation to marker rs11209026. (b) Chromosome 2p15 region. SNP association plot for a 295-kb region (62,300 kb to 62,595 kb) of chromosome 2. LD is in relation to marker rs10865331. (c) Chromosome 5q15 region. SNP association plot for a 258-kb region (96,000 kb to 96,258 kb) of chromosome 5. LD is in relation to marker rs30187. (d) Chromosome 21q22 region. SNP association plot for a 245-kb region (39,350 kb to 39,595 kb) of chromosome 21. LD is in relation to marker rs2242944.