Fig. 1: Resolving molecular mechanisms at chr21q22.
From: A disease-associated gene desert directs macrophage inflammation through ETS2
a, Disease associations at chr21q22. The red points denote the IBD 99% credible set. Co-localization results for each disease versus IBD. PP.H3, posterior probability of independent causal variants; PP.H4, posterior probability of shared causal variant. b, Immune cell H3K27ac ChIP–seq at chr21q22. IBD GWAS results are shown. NK cells, natural killer cells. rpm, reads per million. c, The ETS2 eQTL in resting monocytes, with co-localization versus IBD association. Macrophage promoter-capture Hi-C (pcHi-C) data at the disease-associated locus. d, Experimental schematic for studying the chr21q22 locus in inflammatory (TPP) macrophages. e, ETS2, BRWD1 and PSMG1 mRNA expression during TPP stimulation, measured using PrimeFlow RNA assays. Data are from one representative donor out of four. f, Relative ETS2, BRWD1 and PSMG1 expression (mean fluorescence intensity (MFI)) in chr21q22-edited macrophages versus unedited cells. n = 4. Data are mean ± s.e.m. Statistical analysis was performed using two-way analysis of variance (ANOVA)). g, SuSiE fine-mapping posterior probabilities for IBD-associated SNPs at chr21q22 (99% credible set). h, Macrophage MPRA at chr21q22. Data are oligo coverage (top), enhancer activity (sliding-window analysis with significant enhancer activity highlighted; middle) and expression-modulating effects of SNPs within the enhancer (bottom). For the box plots, the centre line shows the median, the box limits show the interquartile range, and the whiskers represent the minimum and maximum values. n = 8. False-discovery rate (FDR)-adjusted P values were calculated using QuASAR-MPRA (two-sided). i, Inflammatory macrophage PU.1 ChIP–seq peaks at chr21q22. Bottom, magnification of the location of rs2836882 and the nearest predicted PU.1 motif. j, BaalChIP analysis of allele-specific PU.1 ChIP–seq binding at rs2836882 in two heterozygous macrophage datasets (data are mean ± 95% posterior distribution of allelic balance). Total counts shown as a pie chart. k, Allele-specific ATAC–seq reads at rs2836882 in monocytes from 16 heterozygous donors (including healthy controls and patients with ankylosing spondylitis). Statistical analysis was performed using two-sided Wilcoxon matched-pair tests. l, H3K27ac ChIP–seq data from risk (top) or non-risk (bottom) allele homozygotes at rs2836882. Data are shown from two out of four donors. FDR-corrected P values were calculated using MEDIPS (two-sided). The diagrams in d and e were created using BioRender.
