Genetic loci associated with heart rate variability and their effects on cardiac disease risk.
Nolte IM., Munoz ML., Tragante V., Amare AT., Jansen R., Vaez A., von der Heyde B., Avery CL., Bis JC., Dierckx B., van Dongen J., Gogarten SM., Goyette P., Hernesniemi J., Huikari V., Hwang S-J., Jaju D., Kerr KF., Kluttig A., Krijthe BP., Kumar J., van der Laan SW., Lyytikäinen L-P., Maihofer AX., Minassian A., van der Most PJ., Müller-Nurasyid M., Nivard M., Salvi E., Stewart JD., Thayer JF., Verweij N., Wong A., Zabaneh D., Zafarmand MH., Abdellaoui A., Albarwani S., Albert C., Alonso A., Ashar F., Auvinen J., Axelsson T., Baker DG., de Bakker PIW., Barcella M., Bayoumi R., Bieringa RJ., Boomsma D., Boucher G., Britton AR., Christophersen I., Dietrich A., Ehret GB., Ellinor PT., Eskola M., Felix JF., Floras JS., Franco OH., Friberg P., Gademan MGJ., Geyer MA., Giedraitis V., Hartman CA., Hemerich D., Hofman A., Hottenga J-J., Huikuri H., Hutri-Kähönen N., Jouven X., Junttila J., Juonala M., Kiviniemi AM., Kors JA., Kumari M., Kuznetsova T., Laurie CC., Lefrandt JD., Li Y., Li Y., Liao D., Limacher MC., Lin HJ., Lindgren CM., Lubitz SA., Mahajan A., McKnight B., Zu Schwabedissen HM., Milaneschi Y., Mononen N., Morris AP., Nalls MA., Navis G., Neijts M., Nikus K., North KE., O'Connor DT., Ormel J., Perz S., Peters A., Psaty BM., Raitakari OT., Risbrough VB., Sinner MF., Siscovick D., Smit JH., Smith NL., Soliman EZ., Sotoodehnia N., Staessen JA., Stein PK., Stilp AM., Stolarz-Skrzypek K., Strauch K., Sundström J., Swenne CA., Syvänen A-C., Tardif J-C., Taylor KD., Teumer A., Thornton TA., Tinker LE., Uitterlinden AG., van Setten J., Voss A., Waldenberger M., Wilhelmsen KC., Willemsen G., Wong Q., Zhang Z-M., Zonderman AB., Cusi D., Evans MK., Greiser HK., van der Harst P., Hassan M., Ingelsson E., Järvelin M-R., Kääb S., Kähönen M., Kivimaki M., Kooperberg C., Kuh D., Lehtimäki T., Lind L., Nievergelt CM., O'Donnell CJ., Oldehinkel AJ., Penninx B., Reiner AP., Riese H., van Roon AM., Rioux JD., Rotter JI., Sofer T., Stricker BH., Tiemeier H., Vrijkotte TGM., Asselbergs FW., Brundel BJJM., Heckbert SR., Whitsel EA., den Hoed M., Snieder H., de Geus EJC.
Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74<rg<-0.55) and blood pressure (-0.35<rg<-0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.