Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.
Lin H., van Setten J., Smith AV., Bihlmeyer NA., Warren HR., Brody JA., Radmanesh F., Hall L., Grarup N., Müller-Nurasyid M., Boutin T., Verweij N., Lin HJ., Li-Gao R., van den Berg ME., Marten J., Weiss S., Prins BP., Haessler J., Lyytikäinen L-P., Mei H., Harris TB., Launer LJ., Li M., Alonso A., Soliman EZ., Connell JM., Huang PL., Weng L-C., Jameson HS., Hucker W., Hanley A., Tucker NR., Chen Y-DI., Bis JC., Rice KM., Sitlani CM., Kors JA., Xie Z., Wen C., 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 X., Taylor KD., Sotoodehnia N., Rotter JI., Mook-Kanamori DO., Trompet S., Rivadeneira F., Uitterlinden A., Eijgelsheim M., Padmanabhan S., Smith BH., Völzke H., Felix SB., Homuth G., Völker U., Mangino M., Spector TD., Bots ML., Perez M., Kähönen M., Raitakari OT., Gudnason V., Arking DE., Munroe PB., Psaty BM., van Duijn CM., Benjamin EJ., Rosand J., Samani NJ., Hansen T., Kääb S., Polasek O., van der Harst P., Heckbert SR., Jukema JW., Stricker BH., Hayward C., Dörr M., Jamshidi Y., Asselbergs FW., Kooperberg C., Lehtimäki T., Wilson JG., Ellinor PT., Lubitz SA., Isaacs A.
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.