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Additional file 1: Figure S1. Analysis of effect of methotrexate on TL1A levels from a second independent patient cohort. TL1A was measured in serum from an independent cohort of patients with RA treated with MTX for 4 months (66 good/moderate EULAR responders, 18 non-responders).

Additional file 2: Figure S2. Micro-CT Scoring system for erosions and joint damage (MCTS). A scoring system was devised for micro-CT measurements of hind paw joint scores incorporating a score for the ankle/tarsus, MTP, and distal joints with a total score of 0–30 points.

Additional file 3: Table S1. Demographic characteristics of SNUH cohort (data shown in Fig. 2 D-F and Fig. 3 B-D). Sr, serum; SF, synovial fluid; ESR, erythrocyte sedimentation rate; hsCRP, high sensitive C-reactive protein; RF, rheumatoid factor. Table S2. Demographic characteristics of patient subgroups from the SERA cohort.

Trans-eQTLs that overlap RA risk loci on chromosome 6. Genome browser view showing eQTL peaks for three genes associated distally with RA GWAS loci in the HLA region. For each gene, the most significant eQTLs are shown. The color of the eQTL markers corresponds to LD r2 in reference to the strongest eQTL for each gene (as labeled and data shown to the right). The yellow highlights the position of the strongest eQTL for each gene. Histone modification tracks show the fold-change between ChIP and control read counts. Active histone modifications have red bars next to their labels while repressive marks have blue. (PDF 7709 kb)

Comparison of RA cis-eQTLs identified in this study to previously published eQTL studies. The eQTLs mapped in this study (“current study, RA blood”) were compared to those from three published studies, labeled by the first author of each study and the cell type or tissues where gene expression was measured. When compared to the current study, each previous study replicated between ~25 % and 50 % of egenes A and up to ~30 % of eQTL SNPs B reflecting the higher number of SNPs used in this study based on whole-genome sequencing versus the previous studies. When comparing the current study with the previous studies as references, between ~40 % and 60 % of egenes repeated C and ~30 % to 50 % of eQTL SNPs replicated D. (PDF 7622 kb)

Heatmap of genes identified to overlap blood enhancers and RA GWAS loci. Heatmap of genes associated with RA GWAS SNPs in primary monocyte, B cell, or T cell datasets. In addition to the associations from overlapping enhancers and eQTLs (as shown in Fig. 3b), genes that overlap RA GWAS loci in the given cell-type datasets are shown. (PDF 7638 kb)

PADI4 is active in monocytes but not T cells or B cells. Genome browser view of the PADI4 region with tracks from peripheral blood datasets. Histone modification tracks show the fold-change between ChIP and control read counts. Active histone modifications have red bars next to their labels while repressive marks have blue. Genes on the positive and negative strands are shown in blue and cyan, respectively. (PDF 7791 kb)

Fold-enrichment of RA eQTLs in chromatin states of diverse tissues. A The full results from analysis of 97 datasets. A subset of the full results was shown in Fig. 2c. Both cis- and trans-eQTLs were compared to positions of the following chromatin states in diverse tissues: active transcription start sites (TSS), actively transcribed (Tx), enhancers (Enh), active enhancers (EnhA), heterochromatin (Het), bivalent enhancers (EnhBiv), bivalent/poised TSS (TssBiv), repressed Polycomb (ReprPC), and quiescent/low (Quies) regions. PB, peripheral blood. B Results from enrichment analysis with peak eQTLs performed using the goshifter method. The values given are the p values from permutation and the enrichment in parentheses (number of SNPs overlapping the annotation divided by the total number of SNPs). C Enrichment of peak eQTLs in H3K27ac stratified on annotations in other cell types performed using the goshifter method. The p values from permutation are shown. (PDF 7890 kb)

Genes associated with RA GWAS in T cell specific epigenomic datasets. Heatmap of genes associated with RA GWAS SNPs overlapping enhancers in the shown T cell datasets. PB, peripheral blood. Two T cell epigenomes uniquely identify genes that might be explained by unique aspects of the selection markers and (when carried out) in vitro differentiation protocols: (1) “Primary T cells from PB” was the only T cell sample to use CD3+ as a selection marker; and (2) “Primary T helper cells PMA-I stimulated” was the only sample that used Magnetic-activated cell sorting (MACS) [5]. The differences between the two “Primary T helper memory cells from PB” samples might be explained by their different differentiation protocols (number 1 uniquely used CD25M and CD45RO as selection markers) or by the differing donors of origin [5]. (PDF 7665 kb)

Supplemental material. PDF file containing supplemental figures and descriptions (PDF 5120 kb)