Fig. 5: The ATP2B4 association is driven by an erythrocyte-specific transcription start site.

a Normalized RNA-seq coverage for (1) 56 cell types from Roadmap Epigenomics²⁹ and ENCODE, (2) human CD34⁺ hematopoietic stem and progenitor cells, and experimentally differentiated erythroid cells from three biological replicates³¹, (3) ex-vivo differentiated adult and fetal human erythroblasts from 24 individuals³² and (4) experimentally differentiated erythroid progenitor cells and circulating erythrocytes⁴⁵. Coverage is shown across expanded regions of ATP2B4 exon 1, exon 2 including the putative alternative first exon (located at 203,651,123–203,651,366) and the remaining exons. Throughout, red features are those lying within 500 bp upstream to 50 bp downstream of the alternative first exon. For Roadmap and ENCODE data, the plot reflects normalized coverage maximized across cell types in each tissue group. For other cells, coverage is summed over samples and normalized by the mean across ATP2B4 exons. b ATP2B4 transcripts from the GENCODE⁴¹ and FANTOM5⁴⁴ transcript models. c Posterior evidence for association with SM assuming a single causal variant. d Position of GATA1-binding peaks²⁸. e Location and size of the expanded regions shown against the full-length transcript, with GATA1-binding peaks shown. f Posterior evidence for association with SM as in c and with mean corpuscular haemoglobin concentration (MCHC)³⁶, assuming a single causal variant for each trait separately. g Estimated effect of rs10751451 on each exon of ATP2B4, computed by linear regression against FPKM residuals after correcting for cell development stage³², with 95% confidence intervals shown. For comparable visualization across exons, FPKM is further normalized by the mean across samples at each exon. h Mendelian randomization analysis of SM and MCHC at 2130 ‘sentinel’ SNPs previously identified as associated with haematopoetic traits³⁶ with association results in our study. Points reflect the posterior effect-size estimates on SM (y axis) and MCHC (x axis), conditional on the fitted bivariate Gaussian model of effect sizes. Variants are assumed to act independently. Blue solid and dotted lines and text show the maximum likelihood estimate of the effect of MCHC on SM (ρ), its 95% confidence interval, and likelihood ratio test P-value against the null that ρ = 0.