Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation.
Weng L-C., Hall AW., Choi SH., Jurgens SJ., Haessler J., Bihlmeyer NA., Grarup N., Lin H., Teumer A., Li-Gao R., Yao J., Guo X., Brody JA., Müller-Nurasyid M., Schramm K., Verweij N., van den Berg ME., van Setten J., Isaacs A., Ramírez J., Warren HR., Padmanabhan S., Kors JA., de Boer RA., van der Meer P., Sinner MF., Waldenberger M., Psaty BM., Taylor KD., Völker U., Kanters JK., Li M., Alonso A., Perez MV., Vaartjes I., Bots ML., Huang PL., Heckbert SR., Lin HJ., Kornej J., Munroe PB., van Duijn CM., Asselbergs FW., Stricker BH., van der Harst P., Kääb S., Peters A., Sotoodehnia N., Rotter JI., Mook-Kanamori DO., Dörr M., Felix SB., Linneberg A., Hansen T., Arking DE., Kooperberg C., Benjamin EJ., Lunetta KL., Ellinor PT., Lubitz SA.
BACKGROUND: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. METHODS: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. RESULTS: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk. CONCLUSIONS: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.