A1 Refereed original research article in a scientific journal
Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval
Authors: Lin HH, van Setten J, Smith AV, Bihlmeyer NA, Warren HR, Brody JA, Radmanesh F, Hall L, Grarup N, Muller-Nurasyid M, Boutin T, Verweij N, Lin HJ, Li-Gao RF, van den Berg ME, Marten J, Weiss S, Prins BP, Haessler J, Lyytikainen LP, Mei H, Harris TB, Launer LJ, Li M, Alonso A, Soliman EZ, Connell JM, Huang PL, Weng LC, Jameson HS, Hucker W, Hanley A, Tucker NR, Chen YDI, Bis JC, Rice KM, Sitlani CM, Kors JA, Xie ZJ, Wen CP, Magnani JW, Nelson CP, Kanters JK, Sinner MF, Strauch K, Peters A, Waldenberger M, Meitinger T, Bork-Jensen J, Pedersen O, Linneberg A, Rudan I, de Boer RA, van der Meer P, Yao J, Guo XQ, Taylor KD, Sotoodehnia N, Rotter JI, Mook-Kanamori DO, Trompet S, Rivadeneira F, Uitterlinden A, Eijgelsheim M, Padmanabhan S, Smith BH, Volzke H, Mangino M, Spector TD, Bots ML, Perez M, Kahonen M, Raitakari OT, Gudnason V, Arking DE, Munroe PB, Psaty BM, van Duijn CM, Benjamin EJ, Rosand J, Samani NJ, Hansen T, Kaab S, Polasek O, van der Harst P, Heckbert SR, Jukema JW, Stricker BH, Hayward C, Dorr M, Jamshidi Y, Asselbergs FW, Kooperberg C, Lehtimaki T, Wilson JG, Ellinor PT, Lubitz SA, Isaacs A
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Publication year: 2018
Journal: Circulation: Genomic and Precision Medicine
Journal name in source: CIRCULATION-GENOMIC AND PRECISION MEDICINE
Journal acronym: CIRC-GENOM PRECIS ME
Article number: UNSP e002037
Volume: 11
Issue: 5
Number of pages: 11
ISSN: 2574-8300
eISSN: 2574-8300
DOI: https://doi.org/10.1161/CIRCGEN.117.002037
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<1.2x10(-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=5.9x10(-11)) and SCN5A (P=1.1x10(-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.
