Genome-Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study)

Abstract

Background: ECG global electrical heterogeneity (GEH) is associated with sudden cardiac death. We hypothesized that a genome-wide association study would identify genetic loci related to GEH.

Methods and results: We tested genotyped and imputed variants in black (N=3057) and white (N=10 769) participants in the ARIC (Atherosclerosis Risk in Communities) study and CHS (Cardiovascular Health Study). GEH (QRS-T angle, sum absolute QRST integral, spatial ventricular gradient magnitude, elevation, azimuth) was measured on 12-lead ECGs. Linear regression models were constructed with each GEH variable as an outcome, adjusted for age, sex, height, body mass index, study site, and principal components to account for ancestry. GWAS identified 10 loci that showed genome-wide significant association with GEH in whites or joint ancestry. The strongest signal (rs7301677, near TBX3) was associated with QRS-T angle (white standardized β+0.16 [95% CI 0.13-0.19]; P=1.5×10^-26), spatial ventricular gradient elevation (+0.11 [0.08-0.14]; P=2.1×10^-12), and spatial ventricular gradient magnitude (-0.12 [95% CI -0.15 to -0.09]; P=5.9×10^-15). Altogether, GEH-SNPs explained 1.1% to 1.6% of GEH variance. Loci on chromosomes 4 (near HMCN2), 5 (IGF1R), 11 (11p11.2 region cluster), and 7 (near ACTB) are novel ECG phenotype-associated loci. Several loci significantly associated with gene expression in the left ventricle (HMCN2 locus-with HMCN2; IGF1R locus-with IGF1R), and atria (RP11-481J2.2 locus-with expression of a long non-coding RNA and NDRG4).

Conclusions: We identified 10 genetic loci associated with ECG GEH. Replication of GEH GWAS findings in independent cohorts is warranted. Further studies of GEH-loci may uncover mechanisms of arrhythmogenic remodeling in response to cardiovascular risk factors.

Keywords: ECG; electrocardiography; genome wide association study; global electrical heterogeneity; spatial ventricular gradient; sum absolute QRST integral.

Figure 1

Measurement of GEH. A, Spatial QRS‐T angle represents the angle between the QRS‐vector and T‐vector in three‐dimensional space. B, Spatial ventricular gradient (SVG) is a vector defined as the vector sum of the QRS‐vector and the T‐vector. SVG magnitude is the length of the SVG‐vector. SVG azimuth is the angle of the SVG‐vector projected onto the XY (horizontal) plane, and SVG elevation is the angle of the SVG‐vector projected in the XZ (vertical) plane. C, SAI QRST represents the sum of the area under the QRS complex and T‐wave using the isoelectric line as the reference (shaded area). X‐, Y‐, and Z‐lead QRS‐T complexes and their calculated SAI QRST results are shown.

Figure 2

Manhattan plots of the GWAS meta‐analyses for (A) sum absolute QRS‐T integral (SAI QRST), (B) spatial ventricular gradient (SVG) magnitude, (C) SVG azimuth, (D) SVG elevation, and (E) spatial QRS‐T angle in individuals of both white and black ancestry. The dotted horizontal line represents the genome‐wide significance threshold.

Figure 3

Comparison of the association of index SNPs markers with global electrical heterogeneity (GEH) ECG phenotypes in 10 loci in 2 cohorts: (A) ARIC and (B) CHS. Associations in ARIC are shown by a blue square; in CHS—by a purple circuit. SU, standardized units (per 1 standard deviation of ECG trait). ARIC indicates Atherosclerosis Risk in Communities Study; CHS, Cardiovascular Health Study.

Figure 4

Forest plots for the association of index SNPs markers with 5 global electrical heterogeneity (GEH) ECG phenotypes in 10 loci. Associations for white (square), black (diamond) individuals, and joint ancestries (circuit) are shown. Red color indicates associations with SAI QRST; green color—with SVG magnitude; dark navy—with SCG azimuth; magenta color—with SVG elevation; blue color—with spatial QRS‐T angle. SU, standardized units (per 1 standard deviation of ECG trait). A, Locus 1. B, Locus 2. C, Locus 3. D, Locus 4. E, Locus 5. F, Locus 6. G, Locus 7. H, Locus 8. I, Locus 9. J, Locus 10.

Figure 5

Regional association plots show association results at each significantly associated locus. Ten loci are displayed in the order listed in Table 1. Each SNP is plotted with respect to its chromosomal location ±500 kb (X‐axis) and its P‐value (Y‐axis on the left). Known gene transcripts are annotated at the bottom. The SNPs are colored according to their degree of linkage disequilibrium (r ²). The index SNP is shown as a purple diamond. The tall blue spikes indicate the recombination rate (Y‐axis on the right) at that region of the chromosome. A, Locus 1. B, Locus 2. C, Locus 3. D, Locus 4. E, Locus 5. F, Locus 6. G, Locus 7. H, Locus 8. I, Locus 9. J, Locus 10.