Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits

Setten, Jessica van; Verweij, Niek; Mbarek, Hamdi; Niemeijer, Maartje N.; Trompet, Stella; Arking, Dan E.; Brody, Jennifer A.; Gandin, Ilaria; Grarup, Niels; Hall, Leanne; Hemerich, Daiane; Lyytikäinen, Leo Pekka; Mei, Hao; Müller‐Nurasyid, Martina; Prins, Bram P.; Robino, Antonietta; Smith, Albert V.; Warren, Helen R.; Asselbergs, Folkert W.; Boomsma, Dorret I.; Caulfield, Mark J.; Eijgelsheim, Mark; Ford, Ian; Hansen, Torben; Harris, Tamara B.; Heckbert, Susan R.; Hottenga, Jouke Jan; Iorio, Annamaria; Kors, Jan A.; Linneberg, Allan; Macfarlane, Peter W.; Meitinger, Thomas; Nelson, Christopher P.; Raitakari, Olli T.; Aldana, Claudia Tamar Silva; Sinagra, Gianfranco; Sinner, Moritz F.; Soliman, Elsayed Z.; Stoll, Monika; Uitterlinden, André G.; Duijn, Cornelia M. van; Waldenberger, Mélanie; Alonso, Álvaro; Gasparini, Paolo; Gudnason, Vilmundur; Jamshidi, Yalda; Kääb, Stefan; Kanters, Jørgen K.; Lehtimäki, Terho; Munroe, Patricia B.; Peters, Annette; Samani, Nilesh J.; Sotoodehnia, Nona; Ulivi, Sheila; Wilson, James G.; Geus, Eco J. C. de; Jukema, J. Wouter; Stricker, Bruno H.; Harst, Pim van der; Bakker, Paul I. W. de; Isaacs, Aaron

doi:10.1038/s41431-018-0295-z

Cited by 34 publications

(38 citation statements)

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“…To summarise, in meta-analyses of nearly 300,000 individuals we identified 210 loci, of which 149 were novel, underlying cardiac conduction as manifested by the electrocardiographic PR interval. Apart from confirming well-established associations in loci harbouring ion-channel genes, our findings further underscore the central importance of heart development and cytoskeletal components in atrioventricular conduction 10,12,13 . We also highlight the role of common variation at loci harboring genes underlying monogenic forms of heart disease in cardiac conduction.…”

Section: Main Textsupporting

confidence: 79%

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

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Weng

Cartwright

et al. 2019

Preprint

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The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality1,2. We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, discovering 210 loci of which 149 are novel. Variants at all loci nearly doubled the percentage of heritability explained, from 33.5% to 62.6%. We observed enrichment for genes involved in cardiac muscle development/contraction and the cytoskeleton highlighting key regulation processes for atrioventricular conduction. Additionally, 19 novel loci harbour genes underlying inherited monogenic heart diseases suggesting the role of these genes in cardiovascular pathology in the general population. We showed that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease risk, including distal conduction disease, AF, atrioventricular pre-excitation, non-ischemic cardiomyopathy, and coronary heart disease. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

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Section: Main Textsupporting

confidence: 79%

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

Ντάλλα

Weng

Cartwright

et al. 2019

Preprint

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“…The PR interval also serves as a risk factor for atrial fibrillation and cardiovascular mortality [1][2][3] . Prior genetic association studies have identified 64 PR interval loci [4][5][6][7][8][9][10][11][12][13] . Yet the underlying biological mechanisms of atrioventricular conduction and relationships between genetic predisposition to PR interval duration and disease are incompletely characterized.…”

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confidence: 99%

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

et al. 2020

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The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

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“…Given that the minor allele was associated with a worse outcome in both discovery and validation cohorts, one could postulate that an increased expression of SGIP1 and a decreased expression of TCTEX1D1 could be deleterious for the cardiac phenotype in patients with DMD. Interestingly, a recent GWA meta-analysis for quantitative electrocardiography traits, showed that variants in the TCTEX1D1/SGIP1 locus are associated with QT interval [45]. More research (e.g.…”

Section: Discussionmentioning

confidence: 99%

TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy

Spitali

Zaharieva²,

Böhringer

et al. 2020

Eur J Hum Genet

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Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the DMD gene leading to the lack of dystrophin. Variability in the disease course suggests that other factors influence disease progression. With this study we aimed to identify genetic factors that may account for some of the variability in the clinical presentation. We compared whole-exome sequencing (WES) data in 27 DMD patients with extreme phenotypes to identify candidate variants that could affect disease progression. Validation of the candidate SNPs was performed in two independent cohorts including 301 (BIO-NMD cohort) and 109 (CINRG cohort of European ancestry) DMD patients, respectively. Variants in the Tctex1 domain containing 1 (TCTEX1D1) gene on chromosome 1 were associated with age of ambulation loss. The minor alleles of two independent variants, known to affect TCTEX1D1 coding sequence and induce skipping of its exon 4, were associated with earlier loss of ambulation. Our data show that disease progression of DMD is affected by a new locus on chromosome 1 and demonstrate the possibility to identify genetic modifiers in rare diseases by studying WES data in patients with extreme phenotypes followed by multiple layers of validation.

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Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits

Cited by 34 publications

References 50 publications

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy

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