LOD plot of PR interval (black, left y-axis) and <i>Tnni3k (purple</i> right y-axis) on chromosome 3.

<p>LOD plot of PR interval (black, left y-axis) and <i>Tnni3k (purple</i> right y-axis) on chromosome 3.</p

Tnni3k protein levels.

<p>Immunoblot of atrial (A) and ventricular (V) protein lysates of AKR/J and DBA/2J mice using α-mTnni3k and α-ILK as loading control.</p

eQTLs overlapping the 1.5 LOD drop region of the PR QTL.

<p>Transcripts with a significant linkage overlapping the 1.5 LOD drop region of the PR QTL are listed with their genomic location (build NCBIM37), specific LOD score, marker with the highest LOD score, Spearmans correlation to PR (Rho and uncorrected p value). Transcripts with a significant correlation are marked in bold; <i>Tnni3k</i> is marked in bold and underlined.</p

Genotype effects at rs13477506.

<p>(A) <i>Tnni3k</i> expression (Illumina probe ILMN_3023962) as a function of genotype at rs13477506 in F2 mice; homozygous 129P2: AA, green; 129P2-FVBN/J heterozygous: AB, turquoise; homozygous FVBN/J: BB, blue; the darker shades represent the independent validation of the <i>Tnni3k</i> transcription levels by Q-PCR (right y-axis). (B) PR interval as a function of genotype at rs13477506 in F2 mice. Error bars indicate standard errors.</p

Overview of the locations of the linkage regions on chromosome 3.

<p>(A) Entire mouse chromosome 3 with refseq genes indicated in dark blue, black bar: 1.5 LOD drop of the PR-QTL; dark red bar 20 Mb DBA.AKR congenic region; purple bar 1.5 LOD drop of the Tnni3k eQTL; grey bar minimal region of overlap. (B) 1 Mb close up of the minimal region of overlap; the positions of rs49812611 (associated with nonsense mediated decay in DBA/2J) and rs13477506 (QTLs) are indicated. (C) Haplotypes of a panel of 9 inbred mouse strains as determined by the mouse phylogeny viewer (<a href="http://msub.csbio.unc.edu/" target="_blank">http://msub.csbio.unc.edu/</a>) <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003113#pgen.1003113-Yang1" target="_blank">[19]</a>.</p

Overview of the ECG results mean (st.err) in DBA/2J, DBA.AKR.<i>hrtfm2</i> and transgenic <i>hTnni3k</i> mice.

*<p>denotes the values significantly different from DBA/2J in the Bonferroni corrected post hoc analysis at the 0.05 significance level.</p

<i>In silico</i> and <i>in vivo</i> correlation of <i>Tnni3k</i> levels and PR interval duration.

<p>(A) <i>In silico</i> analysis: mouse inbred lines are colored based on the haplotypes in the minimal region of overlap; PR interval duration obtained from the mouse phenome database (<a href="http://phenome.jax.org/" target="_blank">http://phenome.jax.org/</a>) FVBN/J (blue) (low expression) and green (high <i>Tnni3k</i> expression), inbred lines with the reddish colors carry rs49812611 (associated with nonsense mediated decay). (B) <i>In vivo</i> analysis of <i>Tnni3k</i> expression levels (y-axis) and PR interval duration (x-axis) in six inbred mouse lines, colors again denote the haplotype (gray is unknown haplotype).</p

<i>Tnni3k</i> prolongs the PR interval.

<p>(A) Congenic mice carrying the AKR/J green haplotype in a DBA/2J genetic background display the green haplotype PR interval duration. Overexpression of tagged <i>hTNNI3k</i> in a DBA/2J background significantly prolongs the PR interval. Colors show the haplotype of each strain at the <i>Tnni3k</i> locus, error bars indicate standard deviations. (B–D) Examples of ECG traces of DBA/2J (B), AKR.DBA.<i>hrtfm2</i> congenic (C) and DBA/2J overexpressing h<i>TNNI3K</i> (D).</p

Overview plots for top <i>cis</i> eQTLs.

<p>An overview of the 4 most significant <i>cis</i> eQTLs: rs11150882 with <i>C17orf97</i> (panel A), rs11158569 with <i>CHURC1</i> (panel B), rs2779212 with <i>ZSWIM7</i> (panel C) and rs2549794 with <i>ERAP2</i> (panel D). On the left of each panel, box-and-whisker plots of mRNA levels for all genotypes. On the right, mean and standard-error plots of mRNA levels for all genotypes are illustrated. Right upper corner gives the association p-value and the gene name.</p

Look-up of SNPs from cardiac GWAS in eQTL data.

<p>Overview of eQTL effects of reported cardiac electric trait related GWAS SNPs. Only GWAS SNPs reaching genome-wide significance as stated in the original studies (p-value ≤5×10⁻⁸) and with nominal eQTL association (p≤0.05) are reported. This resulted in 34 independent loci. <i>PRKCA</i> (<i>rs9912468</i>, QRS duration) reaches genome-wide significance (4×10⁻⁸; represented in bold in table). The beta is defined as the effect size per copy of the minor allele. LD  =  linkage disequilibrium, TSS  =  transcription start site, Chr.  =  chromosome, Y  =  yes, N  =  no.</p