Supplementary Figure 8: Functional characterization of candidate causal variants at four loci associated with heart rate.

(a, d, f, h) For each of the four loci, the top panel shows the regional plot of association P-values with heart rate (den Hoed, M. et al. Nat. Genet. 45, 621-631, 2013); SNPs are color coded based on r² values from the 1000 Genome Project CEU population (Johnson, A. D. et al. Bioinformatics, 24, 2938-2939, 2008); lead GWAS variants in the locus are indicated by a diamond. The second panel shows the posterior probability of causality (PPA) of the variants in the locus calculated using fgwas, and panels three through five show epigenetic tracks from iPSC-CM combined samples (NKX2-5, ATAC-seq and H3K27a). The bottom panel shows the Roadmap fetal heart ChromHMM and genes from UCSC genome browser (conventional ChromHMM color code). For d and h, the bottom panel shows the locus at lower scale. For d, f and h, the locations of Hi-C loops from iPSC-CM are shown in red. For the candidate causal variants (turquoise lines), the allelic imbalance (pie chart) of NKX2-5 ASE and FRD-corrected P-values are shown; for a, the altered TF motif is shown. Significant associations (P < 0.05, linear regression) between putative variants genotypes and normalized gene expression of candidate genes in iPSC-CMs from 128 different individuals from iPSCORE are shown (c, e, g, i). Boxplot elements: median (thick line), lower and upper quartiles (box), maximum and minimum (whiskers). (b) EMSA with iPSC-CM nuclear extract using probes containing both allelic variants of rs7612445. An independent replicate is shown in Supplementary Figure 9.