Fig. 4: Lupus risk allele-dependent gene regulatory mechanisms at the C4A and SYNGR1 genomic loci.

a, e Normalized MPRA enhancer activity of each experimental replicate for rs3101018 and rs26069235. b, f Expression trait quantitative loci (eQTLs) revealing genotype-dependent expression of C4A and SNYGR1 for rs3101018 (CC, n = 127 biologically independent samples; CT, n = 17; TT, n = 3) and rs26069235 (GG, n = 72 biologically independent samples; GA, n = 66; AA, n = 9) in EBV-transformed B cell lines (GTEx). c, g Genotype-dependent activity of transcription factors, transcriptional regulators, and histone marks in EBV-transformed B cell lines for rs3101018 and rs26069235. Results with MARIO ARS value >0.4 and consistent allelic imbalance across ChIP-seq datasets are included (see “Methods”). The X-axis indicates the preferred allele, along with a value indicating the strength of the allelic behavior, calculated as one minus the ratio of the weak to strong read counts (e.g., 0.5 indicates the strong allele has twice the reads of the weak allele). The median value is plotted when data from multiple cell lines are available, with full results provided in Supplementary Fig. 4. The numbers in parentheses represent the number of ChIP-seq datasets with significant allelic activity (i.e., MARIO ARS value >0.4) out of the number of datasets where the given variant is inside a ChIP-seq peak and is also heterozygous in the given cell line. Variant overlapping TFs are indicated in black. Variant adjacent TFs are shown in green (see definition in Fig. 5a). d, h DNA-binding motif logos are shown for the ATF/CREB/CREM family, and ELF1 in the context of the DNA sequence surrounding rs3101018 and rs2069235, respectively. Tall nucleotides above the X-axis indicate preferred DNA bases. Bases below the X-axis are disfavored. In (b) and (f), data are represented as a violin plot where the middle line is the median, the lower and upper hinges correspond to the first and third quartiles, with the rotated kernel density plot shown on each side. The data used for the analyses were obtained from the Genotype-Tissue Expression (GTEx) Portal on 11/12/2020. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.