Sjögren’s syndrome is a common autoimmune disease (~0.7% of European Americans) typically presenting as keratoconjunctivitis sicca and xerostomia. In addition to strong association within the HLA region at 6p21 (Pmeta=7.65×10−114), we establish associations with IRF5-TNPO3 (Pmeta=2.73×10−19), STAT4 (Pmeta=6.80×10−15), IL12A (Pmeta =1.17×10−10), FAM167A-BLK (Pmeta=4.97×10−10), DDX6-CXCR5 (Pmeta=1.10×10−8), and TNIP1 (Pmeta=3.30×10−8). Suggestive associations with Pmeta<5×10−5 were observed with 29 regions including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP amongst others. These results highlight the importance of genes involved in both innate and adaptive immunity in Sjögren’s syndrome.

Explaining the genetics of many diseases is challenging because most associations localize to incompletely characterized regulatory regions. We show that transcription factors (TFs) occupy multiple loci of individual complex genetic disorders using novel computational methods. Application to 213 phenotypes and 1,544 TF binding datasets identifies 2,264 relationships between hundreds of TFs and 94 phenotypes, including AR in prostate cancer and GATA3 in breast cancer. Strikingly, nearly half of the systemic lupus erythematosus risk loci are occupied by the Epstein-Barr virus EBNA2 protein and many co-clustering human TFs, revealing gene-environment interaction. Similar EBNA2-anchored associations exist in multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis, and celiac disease. Instances of allele-dependent DNA binding and downstream effects on gene expression at plausibly causal variants support genetic mechanisms dependent upon EBNA2. Our results nominate mechanisms that operate across risk loci within disease phenotypes, suggesting new paradigms for disease origins.

Rheumatoid arthritis (RA) is a common autoimmune disease with a complex genetic etiology. Herein we identify a single-nucleotide polymorphism (SNP) in the promoter region of FcRH3, a member of the Fc receptor homolog family, that is associated with RA susceptibility (OR=2. 15, P=0.00000085). This polymorphism alters the binding affinity of nuclear factor-κB and regulates NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptFcRH3 expression. High FcRH3 expression on B-cells and augmented autoantibody production were observed in individuals with the disease-susceptible genotype. Associations were also found between the SNP and susceptibility to autoimmune thyroid disease and systemic lupus erythematosus. FcRH3 may thus play a pivotal role in autoimmunity.Rheumatoid arthritis represents one of the most common autoimmune diseases, and is characterized by inflammation of synovial tissue and joint destruction. Although the disease is believed to result from a combination of genetic and environmental factors, the complete etiology of RA has not yet been clarified 1 . While specific haplotypes of human leukocyte antigen (HLA)-DRB1, usually referred to as shared-epitope (SE) sequences 2 , have been repeatedly reported as conferring RA-susceptibility 3,4 , other genetic components are also involved in the pathogenesis of RA 5 . This combination of HLA haplotypes and non-HLA genes accounting for disease susceptibility is also seen in other autoimmune diseases 6-8 . In autoimmune thyroid disease (AITD), for instance, studies have consistently shown that the HLA-DR3 haplotype is associated with disease risk, in addition to a functional haplotype of a non-HLA gene, CTLA4, that has recently been associated with AITD susceptibility 9 .Identification of non-HLA genes associated with RA susceptibility and other autoimmunities seems difficult, due to the low relative risk of disease resulting from these non-HLA genes compared with the strong relative risk from disease-associated HLA haplotypes. In a search for non-HLA determinants of disease susceptibility, whole genome studies have been conducted for both human autoimmune diseases and experimental animal models. These studies have revealed non-random clustering of susceptibility loci for clinically distinct diseases 8,10 . This overlapping of susceptibility loci for multiple autoimmunities suggests the existence of common susceptibility genes in those regions. Intense studies of loci-clustering regions has revealed genes commonly associated with multiple autoimmune diseases, such as CTLA4 on 2q33 (ref. and Idd17 (ref. 25)). Although 1q21-23 is a strong candidate region for RA susceptible genes, as above mentioned, the association of classical FcγRs with disease susceptibility remains controvertial 26,27 . The present study focused on the 1q21-23 region to identify RA-associated genes in Japanese subjects using linkage disequilibrium (LD) mapping. RESULTS Case-control study by SNP-based LD-mapping in 1q21-23To evaluate the extent of association, we a...