Fig. 4

Chromatin conformation assays and CRISPRqtl confirm interactions between BC risk loci and genes that score in functional screens. A Summary of HiChIP chromatin interactions observed between BC risk loci and genes that scored in functional screens, where color scale signifies scaled levels of chromatin interaction scores and count. B Example of chromatin interactions between CCVs and ATF7IP. C The regulatory element carrying the protective alleles of CCVs rs16909788, rs17221259, rs11055880 increase ATF7IP promoter activity. Constructs containing all three SNPs were tested using luciferase reporter assays. PRE mutant 1 contains the protective haplotype with rs11055880 altered to the risk allele. PRE mutant 2 contains the risk haplotype with rs16909788 and rs17221259 altered to protective alleles. Bars show mean luciferase intensity relative to promoter activity and error bars represent 95% confidence intervals. P-values were determined by two-way ANOVA followed by Dunnett’s multiple comparisons test (****p < 0.0001). DATF7IP expression was measured in K5 + /K19 − cells 21 days post infection with CRISPRi sgRNAs targeting the ATF7IP CCV-containing enhancer. E Strategy used for CRISPRqtl experiment. F Z-Scores from CRISPRqtl screen of sgRNAs targeting 50 known TSSs. G Genes identified by CRISPRqtl screen as targets of 16 fine mapped BC risk regions that had an INQUISIT level 1 and a CRISPR functional screens hit. H Example of CRISPRqtl results at the chr12:1,391,331–14,913,931. I Zoom into ATF7IP, showing 5 enhancers that score in CRISPRqtl as regulators of ATF7IP expression