Immune disease heritability mediated by chromatin accessibility in LCLs.

(A-B) Heritability enrichment in accessible regions in LCLs, based on (A) stratified LD score regression (S-LDSC) and (B) the proportion of heritability mediated by caQTLs in LCLs based on mediated expression score regression (MESC). For both, error bars represent jackknife standard errors of the mean. The color of the bars indicates disease type. *: p < 0.003125 (Bonferroni-corrected). (C) Mediated heritability enrichment of accessible regions by peak strength quintile. The strongest peaks are in the 1st quintile, and the weakest peaks are in the 5th quintile. Only enrichment values with FDR < 5% (based on q-value) are shown. (D) Mediated heritability enrichment of accessible regions by histone mark annotation. The percentages in parentheses represent the proportion of accessible regions with the indicated histone mark. Only enrichment values with FDR < 5% (based on q-value) are shown. Color and size of the points are on the same scale as in (C). PBC, primary biliary cholangitis; MS, multiple sclerosis; CEL, celiac disease; RA, rheumatoid arthritis; JIA, juvenile idiopathic arthritis; SLE, systemic lupus erythematosus; CD, Crohn’s disease; UC, ulcerative colitis; IBD, inflammatory bowel disease; ATD, autoimmune thyroid disease; VIT, vitiligo; AST, asthma; ALL, allergies; SCZ, schizophrenia; T2D, type 2 diabetes; CAD, coronary artery disease.

IMD heritability mediated by caQTLs and eQTLs.

(A) h2med / h2SNP estimates of various IMDs for caQTLs, eQTLs, and their union. AID: autoimmune disease. Disease abbreviations along the x-axis are as in Figure 1. (B) Schema of the potential causal relationships between genetic variants, caQTLs, eQTLs, and IMD risk. The two diagrams depict possible h2med / h2SNP trends depending on the causal relationship between caQTLs and eQTLs. (C) Number of IMD-associated loci colocalized with caQTLs or eQTLs. The proportion is out of the total number of IMD-associated (p < 10-6) loci. (D) ELMO1 locus plot showing association to RA, PBC, MS, chromatin accessibility, and ELMO1 expression in LCLs. Purple shading in the gene plot at the bottom indicates the caQTL peak, and the purple diamond is the lead variant (rs60600003) that is within that peak. The other variants are colored by the degree of linkage disequilibrium (LD) with the annotated variant. (E) Enrichment of the Biological Process Gene Ontology (GO) terms of genes in proximity to IMD-colocalized caQTLs without eQTL colocalization.

Effect of peak-to-TSS distance on cis-heritability of caQTLs and eQTLs and IMD heritability.

(A) Distribution of cis-heritability (h2cis) of caQTLs and eQTLs by peak-to-TSS distance quintiles. The ranges of peak-to-TSS distance are shown in parentheses. The comparisons shown on the top (in respective colors) are between the nearest and each subsequent quintile of the respective QTL h2cis distribution (i.e., one-sided Wilcoxon rank-sum test). The comparisons shown on the bottom (in black) are between caQTL and eQTL h2cis distribution (one-sided paired Wilcoxon rank-sum test). *: p < 10-4, **: p < 10-10, ***: p < 10-20, and ns: p > 0.05. (B) Regression estimates and their standard errors of the linear regression model testing the effects of caQTL h2cis and peak-to-TSS distance on eQTL h2cis. Peak-to-TSS distance was expressed in units of 100 kb to neatly visualize the effect size estimates. SE: standard error. (C) Proportion of caQTL-mediated IMD heritability explained by ATAC peaks within various TSS windows. Percentage for each TSS window denotes the proportion of ATAC peaks in that window. Disease abbreviations along the x-axis are as in Figure 1. (D) A model of the relationship between peak-to-TSS distance and power to detect a corresponding caQTL or eQTL. The thickness of the arrows indicates the variant effect size on chromatin accessibility (yellow) or gene expression (blue). TSS, transcription start site; CRE, cis-regulatory element.

Additional colocalization of caQTL-colocalized IMD loci with meta-analyzed LCL eQTL data.

(A) Number of caQTL-colocalized IMD loci that showed eQTL colocalization in LCLs. Disease abbreviations along the x-axis are as in Figure 1. (B) Distribution of peak-to-TSS distance of all caQTL-eQTL pairs and of those colocalized with IMD association. The number of loci in each category is shown in parentheses. *: p < 0.01, ns: p > 0.05. (C) POU3F1 eQTL that became significantly colocalized with RA association by meta-analyzing LCL eQTL data. Purple shading in the gene plot at the bottom indicates the caQTL peak, and the purple diamond is the lead variant (rs60600003) that is within that peak. The other variants are colored by the degree of linkage disequilibrium (LD) with the annotated variant.

Added utility of various immune cell eQTL data.

(A) Number of loci that additionally colocalized with eQTLs by LCL meta-analysis (orange) and immune cell data (cyan) compared to the original analysis with Geuvadis LCL eQTL data (purple). The height of the bar is the proportion of loci with eQTL colocalization out of the total IMD loci with caQTL colocalization in the earlier analysis. Disease abbreviations along the x-axis are as in Figure 1. (B) Relationship between the number of MS GWAS loci with eQTL colocalization and sample size for each eQTL dataset. Meta-analyzed eQTL data are labeled with their cell types. NK cell, natural killer cell; Treg, regulatory T cell.

IMD loci that colocalized with an eQTL in monocytes, but not in LCLs, even though they colocalized with caQTLs in LCLs.

(A) TNFSF15 locus plot showing genetic association to IBD, chromatin accessibility in LCLs, and TNFSF15 expression in LCLs and monocytes. Purple shading in the gene plot at the bottom indicates the caQTL peak, and the purple diamond shows a strongly associated variant (rs7848647) that is within that peak. The other variants are colored by the degree of LD with the annotated variant. (B) Expression levels of genes in LCLs and monocytes colored according to their eQTL colocalization outcome. TPM: transcripts per million. (C) Number of genes with eQTL colocalization in monocytes, but not in LCLs, separated by the gene’s expression level in LCLs (column) and whether it is lower or higher than that in monocytes (row).