Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13

Abstract

Objective: In a genome-wide association study of Caucasian patients with juvenile idiopathic arthritis (JIA), we have previously described findings limited to autoimmunity loci shared by JIA and other diseases. The present study was undertaken to identify novel JIA-predisposing loci using genome-wide approaches.

Methods: The discovery cohort consisted of Caucasian JIA cases (n = 814) and local controls (n = 658) genotyped on the Affymetrix Genome-Wide SNP 6.0 Array, along with 2,400 out-of-study controls. In a replication study, we genotyped 10 single-nucleotide polymorphisms (SNPs) in 1,744 cases and 7,010 controls from the US and Europe.

Results: Analysis within the discovery cohort provided evidence of associations at 3q13 within C3orf1 and near CD80 (rs4688011) (odds ratio [OR] 1.37, P = 1.88 × 10(-6) ) and at 10q21 near JMJD1C (rs647989 [OR 1.59, P = 6.1 × 10(-8) ], rs12411988 [OR 1.57, P = 1.16 × 10(-7) ], and rs10995450 [OR 1.31, P = 6.74 × 10(-5) ]). Meta-analysis provided further evidence of association for these 4 SNPs (P = 3.6 × 10(-7) for rs4688011, P = 4.33 × 10(-5) for rs6479891, P = 2.71 × 10(-5) for rs12411988, and P = 5.39 × 10(-5) for rs10995450). Gene expression data on 68 JIA cases and 23 local controls showed cis expression quantitative trait locus associations for C3orf1 SNP rs4688011 (P = 0.024 or P = 0.034, depending on the probe set) and JMJD1C SNPs rs6479891 and rs12411988 (P = 0.01 or P = 0.04, depending on the probe set and P = 0.008, respectively). Using a variance component liability model, it was estimated that common SNP variation accounts for approximately one-third of JIA susceptibility.

Conclusion: Genetic association results and correlated gene expression findings provide evidence of JIA association at 3q13 and suggest novel genes as plausible candidates in disease pathology.

Figure 1

A. JIA genome-wide association results (−log10[p]) plotted on a genomic scale (Manhattan plot). The horizontal line represents a p-value of 5×10⁻⁸. This conservative threshold for genome-wide significance ignores linkage disequilibrium in this Caucasian cohort. B. Association results for the extended MHC region (chromosome 6, 26-34 Mb). SNPs with P < 0.01 are represented and color-coded by odds ratio (OR) strata. SNPs of interest include (i) rs1035798 (position 32,259,200 bp, gene AGER; OR=2.32, P=9.5 × 10-42); (ii) rs2071286 (position 32,287,874 bp, gene NOTCH4; OR=2.21, P=5.0 × 10-35); (iii) rs10947261 (position 32,481,210 bp, gene BTNL2; OR=2.66, P=1.1 × 10-32); (iv) rs9268858 (position 32,537,736 bp, 17 kb from HLA-DRA; OR=2.70, P=1.9 × 10-32); (v) rs9268853 (position 32,537,621 bp, 17 kb from HLA-DRA; OR=2.70, P=2.3 × 10-32); (vi) rs9366752 (position 30,132,656 Mb, 2 kb from HLA-H; OR=2.14, P=1.9 × 10-21).

Figure 2

Regional plots of JIA loci. Genotyped and imputed SNPs are plotted with their Discovery P-values (−log₁₀[p]) as a function of genomic position (assembly hg18) within a 400 kb region surrounding the most significant SNP (purple diamond). Recombination rates from the HapMap Phase II CEU are plotted in blue to reflect the regional linkage disequilibrium structure. In each region the index SNP is represented by a large purple diamond, and the color of all other SNPs (circles) indicates LD with the index SNP based on pairwise r² values from HapMap CEU (red, r² > 0.8; orange, r² = 0.6-0.8; green, r² = 0.4-0.6; light blue, r² = 0.2-0.4; dark blue, r² < 0.2). SNPs chosen for replication are represented by a triangle. Known human genes in the UCSC Genome Browser are indicated at the bottom of the plot.