Dataset Information

Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.

ABSTRACT: BACKGROUND:Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. METHODS:We performed large-scale meta-analyses of the PR interval that included 83?367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. RESULTS:We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2×10-6), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 (P=5.9×10-11) and SCN5A (P=1.1×10-7) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus. CONCLUSIONS:We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.

SUBMITTER: Lin H

PROVIDER: S-EPMC5951629 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.

Lin Honghuang H van Setten Jessica J Smith Albert V AV Bihlmeyer Nathan A NA Warren Helen R HR Brody Jennifer A JA Radmanesh Farid F Hall Leanne L Grarup Niels N Müller-Nurasyid Martina M Boutin Thibaud T Verweij Niek N Lin Henry J HJ Li-Gao Ruifang R van den Berg Marten E ME Marten Jonathan J Weiss Stefan S Prins Bram P BP Haessler Jeffrey J Lyytikäinen Leo-Pekka LP Mei Hao H Harris Tamara B TB Launer Lenore J LJ Li Man M Alonso Alvaro A Soliman Elsayed Z EZ Connell John M JM Huang Paul L PL Weng Lu-Chen LC Jameson Heather S HS Hucker William W Hanley Alan A Tucker Nathan R NR Chen Yii-Der Ida YI Bis Joshua C JC Rice Kenneth M KM Sitlani Colleen M CM Kors Jan A JA Xie Zhijun Z Wen Chengping C Magnani Jared W JW Nelson Christopher P CP Kanters Jørgen K JK Sinner Moritz F MF Strauch Konstantin K Peters Annette A Waldenberger Melanie M Meitinger Thomas T Bork-Jensen Jette J Pedersen Oluf O Linneberg Allan A Rudan Igor I de Boer Rudolf A RA van der Meer Peter P Yao Jie J Guo Xiuqing X Taylor Kent D KD Sotoodehnia Nona N Rotter Jerome I JI Mook-Kanamori Dennis O DO Trompet Stella S Rivadeneira Fernando F Uitterlinden André A Eijgelsheim Mark M Padmanabhan Sandosh S Smith Blair H BH Völzke Henry H Felix Stephan B SB Homuth Georg G Völker Uwe U Mangino Massimo M Spector Timothy D TD Bots Michiel L ML Perez Marco M Kähönen Mika M Raitakari Olli T OT Gudnason Vilmundur V Arking Dan E DE Munroe Patricia B PB Psaty Bruce M BM van Duijn Cornelia M CM Benjamin Emelia J EJ Rosand Jonathan J Samani Nilesh J NJ Hansen Torben T Kääb Stefan S Polasek Ozren O van der Harst Pim P Heckbert Susan R SR Jukema J Wouter JW Stricker Bruno H BH Hayward Caroline C Dörr Marcus M Jamshidi Yalda Y Asselbergs Folkert W FW Kooperberg Charles C Lehtimäki Terho T Wilson James G JG Ellinor Patrick T PT Lubitz Steven A SA Isaacs Aaron A

Circulation. Genomic and precision medicine 20180501 5

<h4>Background</h4>Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.<h4>Methods</h4>We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 ...[more]

PMID: 29748316

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Project description:ImportanceAtrial fibrillation (AF) has a substantial genetic component. The importance of polygenic risk is well established, while the contribution of rare variants to disease risk warrants characterization in large cohorts.ObjectiveTo identify rare predicted loss-of-function (pLOF) variants associated with AF and elucidate their role in risk of AF, cardiomyopathy (CM), and heart failure (HF) in combination with a polygenic risk score (PRS).Design, setting, and participantsThis was a genetic association and nested case-control study. The impact of rare pLOF variants was evaluated on the risk of incident AF. HF and CM were assessed in cause-specific Cox regressions. End of follow-up was July 1, 2022. Data were analyzed from January to October 2023. The UK Biobank enrolled 502 480 individuals aged 40 to 69 years at inclusion in the United Kingdom between March 13, 2006, and October 1, 2010. UK residents of European ancestry were included. Individuals with prior diagnosis of AF were excluded from analyses of incident AF.ExposuresRare pLOF variants and an AF PRS.Main outcomes and measuresRisk of AF and incident HF or CM prior to and subsequent to AF diagnosis.ResultsA total of 403 990 individuals (218 489 [54.1%] female) with a median (IQR) age of 58 (51-63) years were included; 24 447 were diagnosed with incident AF over a median (IQR) follow-up period of 13.3 (12.4-14.0) years. Rare pLOF variants in 6 genes (TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71) were associated with AF. Of these, TTN, RPL3L, PKP2, CTNNA3, and KDM5B replicated in an external cohort. Combined with high PRS, rare pLOF variants conferred an odds ratio of 7.08 (95% CI, 6.03-8.28) for AF. Carriers with high PRS also had a substantial 10-year risk of AF (16% in female individuals and 24% in male individuals older than 60 years). Rare pLOF variants were associated with increased risk of CM both prior to AF (hazard ratio [HR], 3.13; 95% CI, 2.24-4.36) and subsequent to AF (HR, 2.98; 95% CI, 1.89-4.69).Conclusions and relevanceRare and common genetic variation were associated with an increased risk of AF. The findings provide insights into the genetic underpinnings of AF and may aid in future genetic risk stratification.

Dataset Information

Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.

Publications

Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.

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