Genome-wide association study of PR interval.
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- Authors
- Pfeufer, Arne; van Noord, Charlotte; Marciante, Kristin D; Arking, Dan E; Larson, Martin G; Smith, Albert Vernon; Tarasov, Kirill V; Müller, Martina; Sotoodehnia, Nona; Sinner, Moritz F; Verwoert, Germaine C; Li, Man; Kao, W H Linda; Kâttgen, Anna; Coresh, Josef; Bis, Joshua C; Psaty, Bruce M; Rice, Kenneth; Rotter, Jerome I; Rivadeneira, Fernando; Hofman, Albert; Kors, Jan A; Stricker, Bruno H C; Uitterlinden, André G; van Duijn, Cornelia M; Beckmann, Britt M; Sauter, Wiebke; Gieger, Christian; Lubitz, Steven A; Newton-Cheh, Christopher; Wang, Thomas J; Magnani, Jared W; Schnabel, Renate B; Chung, Mina K; Barnard, John; Smith, Jonathan D; Van Wagoner, David R; Vasan, Ramachandran S; Aspelund, Thor; Eiriksdottir, Gudny; Harris, Tamara B; Launer, Lenore J; Najjar, Samer S; Lakatta, Edward; Schlessinger, David; Uda, Manuela; Abecasis, Gonçalo R; Müller-Myhsok, Bertram; Ehret, Georg B; Boerwinkle, Eric; Chakravarti, Aravinda; Soliman, Elsayed Z; Lunetta, Kathryn L; Perz, Siegfried; Wichmann, H-Erich; Meitinger, Thomas; Levy, Daniel; Gudnason, Vilmundur; Ellinor, Patrick T; Sanna, Serena; KÀÀb, Stefan; Witteman, Jacqueline C M; Alonso, Alvaro; Benjamin, Emelia J; Heckbert, Susan R
- Year
- 2010
- Journal
- Nature genetics
- PMID
- 20062060
- DOI
- 10.1038/ng.517
- PMCID
- PMC2850197
The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.
Manhattan Plot of genome-wide association analyses. Genome-wide association results were combined across all studies by inverse variance weighting. The blue line marks the threshold for genome-wide significance (P= 5Γ10-8). Coordinates are given in NCBI build 36.
Association results at each significant locus. Associated loci are displayed in genomic order from left to right: MEIS1, SCN5A/SCN10A region, ARHGAP24, NKX2-5 region, CAV1/CAV2 region, WNT11, SOX5 region and TBX5/TBX3 region. Each panel spans Β±500 kb around each SNP and has known gene transcripts annotated at the bottom. The SNPs are colored according to their degree of linkage disequilibrium (r2) with the leading variant highlighted with a blue square and displayed by name and achieved significance level in the meta-analysis. The lower right panel shows the QQ plot of the meta-analysis findings with a genomic control factor (Ξ») of 1.076.
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