Figure 3.
Associations with CXCR4. (A) Four independent associations were detected at 2q22. Credible sets (supplemental Table 9) indicated in red (lead variant rs309137), green (rs11688530), cyan (rs555647251), and blue (rs10193623). Using ATAC-seq and PCHi-C data, a single plausible causal variant was identified within each set. rs59222832 (“V2”; in credible set of rs11688530) and rs770321415 (“V3”; in credible set of rs555647251) map to the CXCR4 promoter region, 4.7 and 1.3 kb upstream of the transcription start site, respectively. In the other 2 credible sets, the lead variants rs309137 (“V1”) and rs10193623 (“V4”) were identified as likely causal based on looping interactions with the promoter (red and blue arches; y-axis indicates PCHi-C P-score). (B) Chromatin accessibility at putative causal variants in 18 blood cell types (y-axis indicates ATAC-seq signal): HSCs, MPPs, lymphoid-primed multipotent progenitors (LMPP), common lymphoid progenitors (CLP), common myeloid progenitors (CMP), granulocyte-monocyte progenitors (GMPs), MEPs, monocyte (MONO), megakaryocyte (MEGA), CD4+ T cells (CD4 TCELL), CD8+ T-cells (CD8 TCELL), B cells (BCELL), natural killer cells (NK), myeloid and plasmacytoid dendritic cells (mDC and pDC, respectively), and plasma cells (PC). (C) Conditional CXCR4 cis-eQTLs for the 3 common variants in our CD34+ cell RNA-seq data (n = 155). Wedges indicate directions of effects on blood CD34+ cell levels. Data are residual Fragments Per Kilobase of transcript per Million mapped reads (FPKM) values after correction for the 2 covariate lead variants and 10 principal components. P values for multivariable regression, one-sided in the direction opposite the effect on blood CD34+ cell levels of the illustrated variant. (D) CXCR4 expression in MOLM13 cells subjected to CRISPR/Cas9 editing with empty vector (Vec), a nontargeting sgRNA pair (Ctrl), or sgRNA pairs designed to delete 587 to 1421 bp regions harboring the 4 putative causal variants (3-4 biological replicates per condition) (supplemental Table 4; supplemental Figure 14). a.u., arbitrary units; mRNA, messenger RNA; n.s., not significant; **P < .01.

Associations with CXCR4. (A) Four independent associations were detected at 2q22. Credible sets (supplemental Table 9) indicated in red (lead variant rs309137), green (rs11688530), cyan (rs555647251), and blue (rs10193623). Using ATAC-seq and PCHi-C data, a single plausible causal variant was identified within each set. rs59222832 (“V2”; in credible set of rs11688530) and rs770321415 (“V3”; in credible set of rs555647251) map to the CXCR4 promoter region, 4.7 and 1.3 kb upstream of the transcription start site, respectively. In the other 2 credible sets, the lead variants rs309137 (“V1”) and rs10193623 (“V4”) were identified as likely causal based on looping interactions with the promoter (red and blue arches; y-axis indicates PCHi-C P-score). (B) Chromatin accessibility at putative causal variants in 18 blood cell types (y-axis indicates ATAC-seq signal): HSCs, MPPs, lymphoid-primed multipotent progenitors (LMPP), common lymphoid progenitors (CLP), common myeloid progenitors (CMP), granulocyte-monocyte progenitors (GMPs), MEPs, monocyte (MONO), megakaryocyte (MEGA), CD4+ T cells (CD4 TCELL), CD8+ T-cells (CD8 TCELL), B cells (BCELL), natural killer cells (NK), myeloid and plasmacytoid dendritic cells (mDC and pDC, respectively), and plasma cells (PC). (C) Conditional CXCR4 cis-eQTLs for the 3 common variants in our CD34+ cell RNA-seq data (n = 155). Wedges indicate directions of effects on blood CD34+ cell levels. Data are residual Fragments Per Kilobase of transcript per Million mapped reads (FPKM) values after correction for the 2 covariate lead variants and 10 principal components. P values for multivariable regression, one-sided in the direction opposite the effect on blood CD34+ cell levels of the illustrated variant. (D) CXCR4 expression in MOLM13 cells subjected to CRISPR/Cas9 editing with empty vector (Vec), a nontargeting sgRNA pair (Ctrl), or sgRNA pairs designed to delete 587 to 1421 bp regions harboring the 4 putative causal variants (3-4 biological replicates per condition) (supplemental Table 4; supplemental Figure 14). a.u., arbitrary units; mRNA, messenger RNA; n.s., not significant; **P < .01.

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