PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Setten, Jessica van; Brody, Jennifer A.; Jamshidi, Yalda; Swenson, Brenton R.; Butler, Anne M.; Campbell, Harry; Greco, Fabiola M. Del; Evans, Daniel S.; Gibson, Quince; Guðbjartsson, Daníel F.; Kerr, Kathleen F.; Krijthe, Bouwe P.; Lyytikäinen, Leo-Pekka; Müller, Christian; Müller‐Nurasyid, Martina; Nolte, Ilja M.; Padmanabhan, Sandosh; Ritchie, Marylyn D.; Robino, Antonietta; Smith, Albert V.; Steri, Maristella; Tanaka, Toshiko; Teumer, Alexander; Trompet, Stella; Ulivi, Sheila; Verweij, Niek; Yin, Xiaoyan; Arnar, Davíð O.; Asselbergs, Folkert W.; Bader, Joel S.; Barnard, John; Bis, Josh C.; Blankenberg, Stefan; Boerwinkle, Eric; Bradford, Yuki; Buckley, Brendan M.; Chung, Mina K.; Crawford, Dana C.; Hoed, Marcel den; Denny, Josh C.; Dominiczak, Anna F.; Ehret, Georg; Eijgelsheim, Mark; Ellinor, Patrick T.; Felix, Stephan B.; Franco, Oscar H.; Franke, Lude; Harris, Tamara B.; Hólm, Hilma; Gandin, Ilaria; Iorio, Annamaria; Kähönen, Mika; Kolčić, Ivana; Kors, Jan A.; Lakatta, Edward G.; Launer, Lenore J.; Lin, Honghuang; Lin, Henry J.; Loos, Ruth J.F.; Lubitz, Steven A.; Macfarlane, Peter W.; Magnani, Jared W.; Leach, Irene Mateo; Meitinger, Thomas; Mitchell, Braxton D.; Münzel, Thomas; Papanicolaou, George; Peters, Annette; Pfeufer, Arne; Pramstaller, Peter P.; Raitakari, Olli T.; Rotter, Jerome I.; Rudan, Igor; Samani, Nilesh J.; Schlessinger, David; Aldana, Claudia Tamar Silva; Sinner, Moritz F.; Smith, Jonathan; Snieder, Harold; Soliman, Elsayed Z.; Spector, Timothy D.; Stott, David J.; Strauch, Konstantin; Tarasov, Kirill V.; Þorsteinsdóttir, Unnur; Uitterlinden, André G.; Wagoner, David R. Van; Völker, Uwe; Völzke, Henry; Waldenberger, Mélanie; Westra, Harm Jan; Wild, Philipp S.; Zeller, Tanja; Alonso, Álvaro; Avery, Christy L.; Bandinelli, Stefania; Benjamin, Emelia J.; Cucca, Francesco; Dörr, Marcus; Ferrucci, Luigi; Gasparini, Paolo; Gudnason, Vilmundur; Hayward, Caroline; Heckbert, Susan R.; Hicks, Andrew A.; Jukema, J. Wouter; Kääb, Stefan; Lehtimäki, Terho; Liu, Yongmei; Munroe, Patricia B.; Parsa, Afshin; Polašek, Ozren; Psaty, Bruce M.; Roden, Dan M.; Schnabel, Renate B.; Sinagra, Gianfranco; Stefánsson, Kāri; Stricker, Bruno H.; Harst, Pim van der; Duijn, Cornelia M. van; Wilson, James F.; Gharib, Sina A.; Bakker, Paul I. W. de; Isaacs, Aaron; Arking, Dan E.; Sotoodehnia, Nona

doi:10.1038/s41467-018-04766-9

Cited by 77 publications

(78 citation statements)

References 34 publications

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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%

“…In total, we identified missense variants in genes at 12 novel and 6 previously reported loci ( Supplementary Table 12 ). At MYH6 , a previously described locus for PR interval 6,10 , sick sinus syndrome 16 , AF and other cardiovascular traits 17 , we observed a novel predicted damaging missense variant in MYH6 (rs28711516, p.Gly56Arg). MYH6 encodes the α-heavy chain subunit of cardiac myosin.…”

Section: Main Textmentioning

confidence: 73%

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

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Weng

Cartwright

et al. 2019

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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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confidence: 79%

Section: Main Textmentioning

confidence: 73%

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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“…SPSB3 is involved in degradation of the transcription factor SNAIL, which regulates the epithelialmesenchymal transition 15 , and has not been previously associated with cardiovascular traits. At MYH6, a previously described locus for PR interval 6,10 , sick sinus syndrome 16 , AF and other cardiovascular traits 17 , we observed a previously not reported predicted damaging missense variant in MYH6 (rs28711516, p. Gly56Arg). MYH6 encodes the α-heavy chain subunit of cardiac myosin.…”

Section: Resultsmentioning

confidence: 52%

“…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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“…Recently, TTN was identified as being associated with atrial and atrioventricular electrical activity though genome-wide association study. 19 However, the relationship between TTN and AVB is illusive; the underlying genetic mechanism contributing to the third degree AVB is still not fully characterized. 1,20…”

Section: Introductionmentioning

confidence: 99%

Identification of TTN as a novel candidate gene for atrioventricular block in a Chinese pedigree by whole-exome sequencing

Liu

Yang

Chen

et al. 2018

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Purpose: Cardiovascular diseases are the most common cause of death globally. In which atrioventricular block (AVB) is a common disorder with genetic causes, but the responsible genes have not been fully identified yet. To determine the underlying causative genes involved in cardiac AVB, here we report a three-generation Chinese family with severe autosomal dominant cardiac AVB that has been ruled out as being caused by known genes mutations.Methods: Whole-exome sequencing was performed in five affected family members across three generations, and co-segregation analysis was validated on other members of this family.Results: Whole-exome sequencing and subsequent co-segregation validation identified a novel germline heterozygous point missense mutation, c.49287C>A (p.N16429K), in the titin (TTN, NM_001267550.2) gene in all 5 affected family members, but not in the unaffected family members. The point mutation is predicted to be functionally deleterious by in-silico software tools. Our finding was further supported by the conservative analysis across species.Conclusion: Based on this study, TTN was identified as a potential novel candidate gene for autosomal dominant AVB; this study expands the mutational spectrum of TTN gene and is the first to implicate TTN mutations as AVB disease causing in a Chinese pedigree.

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PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Cited by 77 publications

References 34 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

Identification of TTN as a novel candidate gene for atrioventricular block in a Chinese pedigree by whole-exome sequencing

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