TY - JOUR
T1 - Genome-Wide associations of global electrical heterogeneity ECG phenotype
T2 - The ARIC (Atherosclerosis Risk in Communities) study and CHS (Cardiovascular Health Study)
AU - Tereshchenko, Larisa G.
AU - Sotoodehnia, Nona
AU - Sitlani, Colleen M.
AU - Ashar, Foram N.
AU - Kabir, Muammar
AU - Biggs, Mary L.
AU - Morley, Michael P.
AU - Waks, Jonathan W.
AU - Soliman, Elsayed Z.
AU - Buxton, Alfred E.
AU - Biering-Sørensen, Tor
AU - Solomon, Scott D.
AU - Post, Wendy S.
AU - Cappola, Thomas P.
AU - Siscovick, David S.
AU - Arking, Dan E.
N1 - Funding Information:
The authors thank the staff and participants of the ARIC study and CHS for their important contributions. The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN-268201700003I, HHSN268201700005I, HHSN26820-1700004I, HHSN2682017000021); National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200-800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HHSN268200960009C; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120-393, R01HL130114, and R01HL085251 with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from the National Institute on Aging. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Diseases Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. This work was supported by 1R01HL118277 (Tereshchenko), R01 HL111089 (Sotoodehnia), R01 HL116747 (Sotoodehnia and Arking) and the Laughlin Family.
Publisher Copyright:
© 2018 The Authors.
PY - 2018/4/17
Y1 - 2018/4/17
N2 - Background--ECG global electrical heterogeneity (GEH) is associated with sudden cardiac death. We hypothesized that a genomewide 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.
AB - Background--ECG global electrical heterogeneity (GEH) is associated with sudden cardiac death. We hypothesized that a genomewide 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.
KW - ECG
KW - Electrocardiography
KW - Genome wide association study
KW - Global electrical heterogeneity
KW - Spatial ventricular gradient
KW - Sum absolute QRST integral
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U2 - 10.1161/JAHA.117.008160
DO - 10.1161/JAHA.117.008160
M3 - Article
C2 - 29622589
AN - SCOPUS:85045313819
SN - 2047-9980
VL - 7
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 8
M1 - e008160
ER -