Our genome-wide association study of celiac disease previously identified risk variants in the IL2–IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 × 10⁻⁷). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2–IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways.

Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5×10⁻⁸ in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (P_combined = 1.2×10⁻¹²), rs864537 near CD247 (P_combined = 2.2×10⁻¹¹), rs2298428 near UBE2L3 (P_combined = 2.5×10⁻¹⁰), and rs11203203 near UBASH3A (P_combined = 1.1×10⁻⁸). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5×10⁻⁸ (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases. Celiac disease (CD) and rheumatoid arthritis (RA) are two autoimmune diseases characterized by distinct clinical features but increased co-occurrence in families and individuals. Genome-wide association studies (GWAS) performed in CD and RA have identified the HLA region and 26 non-HLA genetic risk loci in each disease. Of the 26 CD and 26 RA risk loci, previous studies have shown that six are shared between the two diseases. In this study we aimed to identify additional shared risk alleles and, in doing so, gain more insight into shared disease pathogenesis. We first empirically investigated the distribution of putative risk alleles from GWAS across both diseases (after removing known risk loci for both diseases). We found that CD risk alleles are non-randomly distributed in the RA GWAS (and vice versa), indicating that CD risk alleles have an increased prior probability of being associated with RA (and vice versa). Next, we performed a GWAS meta-analysis to search for shared risk alleles by combing the RA and CD GWAS, performing both directional and opposite allelic effect analyses, followed by replication testing in independent case-control datasets in both diseases. In addition to the already established six non-HLA shared risk loci, we observed statistically robust associations at eight SNPs, thereby increasing the number of shared non-HLA risk loci to fourteen. Finally, we used gene expression studies and pathway analysis tools to identify the plausible candidate genes in the fourteen associated loci. We observed remarkable overrepresentation of T-cell signaling molecules among the shared genes.

André Reis and colleagues report a genome-wide association study identifying a susceptibility locus at TRAF3IP2 for psoriatic arthritis and psoriasis. Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10−17). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10−3). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10−20, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.

Objective: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. Design: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p<1×10 ⁻⁰⁴ and were then genotyped in an independent Italian coeliac cohort (538 cases and 593 controls). Results: We identified two novel coeliac disease risk regions: 6q23.3 ( OLIG3-TNFAIP3 ) and 2p16.1 ( REL ), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p = 1.3×10 ⁻⁰⁸ , and rs842647 p = 5.2×10 ⁻⁰⁷ ). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression. Conclusions: Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-κB) inflammatory signalling pathway. For the first time, a role for primary heritable variation in this important biological pathway predisposing to coeliac disease has been identified. Currently, the HLA risk factors and the 10 established non-HLA risk factors explain ∼40% of the heritability of coeliac disease.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified to date are shared with psoriasis. Here, we present results from a case–control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at theIL23Rlocus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8⁺memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA.