KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern

Figures

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  Figure 1. GWAS results for the KCND3 locus. The results of the combined early repolarization pattern (ERP) GWAS results for the KCND3 locus are shown for the replicated discovery-stage lead SNP rs12090194 in n = 38,811 individuals (A and B) and for the combined GWAS lead SNP rs1545300 in n = 38,806 individuals (C and D). The regional association plots (A and C) show the association results in a ±500-kb region around the lead SNP. SNPs are plotted on the x axis according to their chromosomal position with the –log10(P value) of the GWAS association on the y axis. Correlation with the lead SNP (purple) is estimated based on the 1000 Genomes reference samples. Plots were generated using the LocusZoom website (54). Genetic positions refer to GRCh37/hg19 coordinates. Forest plots of the respective lead SNPs are provided in B and D, with ORs and their 95% confidence intervals plotted on the x axis. I2 is the percentage of total variation across studies that is due to heterogeneity.

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  Figure 2. Location of the significantly (P < 5 × 10–8) associated SNPs within the KCND3 gene. The top 43 SNPs with a genome-wide significance visualized by UCSC Genome Browser (55). All 43 SNPs mapped into the KCND3 gene. The 2 leads SNPs, rs1545300 and rs12090194, of the discovery and combined meta-analyses are reported with a red and an orange diamond, respectively. The H3K27Ac mark track (Layered H3K27Ac) shows the levels of enrichment of the H3K27Ac histone mark. Chemical modifications (e.g., methylation and acylation) to the histone proteins present in chromatin influence gene expression by changing how accessible the chromatin is to transcription. The H3K27Ac histone mark is thought to enhance transcription, possibly by blocking the spread of the repressive histone mark H3K27Me3. The GeneHancer (GH) track set shows human regulatory elements, i.e., enhancers (gray) and promoters (red) containing tracks representing regulatory elements (Reg Elems), gene transcription start sites (TSS), associations between regulatory elements and genes (Interactions), and clustered interactions (Clusters). A gray box in the DNaseI hypersensitivity clusters track (DNase Clusters) indicates the extent of…

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  Figure 3. Colocalization results. Illustrations of the SMR test for the early repolarization pattern (ERP) risk and the expression quantitative trait loci (eQTLs) at the rs1545300 locus at chromosome 1p13.2 for the (A) left ventricle of the heart, (B) tibial artery, and (C) minor salivary gland tissue. The sample sizes for the eQTLs are n = 272, n = 388, and n = 85 in A, B, and C, respectively. In A–C, the GWAS regional association plot with ERP risk of the combined GWAS (n = 39,456), with level of significance of the SMR test (y axis) for each transcript in the locus indicated by a diamond positioned at the center of the transcript is shown (top). A significant SMR test represented by a purple diamond indicates an association of the transcript level of the respective genes (purple label) with the trait. For all 3 tissues, an increased gene expression level shown by a significant SMR test was associated with a higher risk of ERP. A filled purple diamond indicates a HEIDI test P > 0.05 and, thus, a likely colocalization. The regional association distribution with changes in expression of the highlighted (purple) gene transcript in the respective tissue is shown below. The x axis shows…