Genetic loci associated with heart rate variability and their effects on cardiac disease risk
Authors: Nolte Ilja M. , Munoz M. Loretto , Tragante Vinicius , Amare Azmeraw T. , Jansen Rick , Vaez Ahmad , von der Heyde Benedikt , Avery Christy L. , Bis Joshua C. , Dierckx Bram , van Dongen Jenny , Gogarten Stephanie M. , Goyette Philippe , Hernesniemi Jussi , Huikari Ville , Hwang Shih-Jen , Jaju Deepali , Kerr Kathleen F. , Kluttig Alexander , Krijthe Bouwe P. , Kumar Jitender , van der Laan Sander W. , Lyytikäinen Leo-Pekka , Maihofer Adam X. , Minassian Arpi , van der Most Peter J. , Müller-Nurasyid Martina , Nivard Michel , Salvi Erika , Stewart James D. , Thayer Julian F. , Verweij Niek , Wong Andrew , Zabaneh Delilah , Zafarmand Mohammad H. , Abdellaoui Abdel , Albarwani Sulayma , Albert Christine , Alonso Alvaro , Ashar Foram , Auvinen Juha , Axelsson Tomas , Baker Dewleen G. , de Bakker Paul I. W. , Barcella Matteo , Bayoumi Riad , Bieringa Rob J. , Boomsma Dorret , Boucher Gabrielle , Britton Annie R. , Christophersen Ingrid , Dietrich Andrea , Ehret George B. , Ellinor Patrick T. , Eskola Markku , Felix Janine F. , Floras John S. , Franco Oscar H. , Friberg Peter , Gademan Maaike G. J. , Geyer Mark A. , Giedraitis Vilmantas , Hartman Catharina A. , Hemerich Daiane , Hofman Albert , Hottenga Jouke-Jan , Huikuri Heikki , Hutri-Kähönen Nina , Jouven Xavier , Junttila Juhani , Juonala Markus , Kiviniemi Antti M. , Kors Jan A. , Kumari Meena , Kuznetsova Tatiana , Laurie Cathy C. , Lefrandt Joop D. , Li Yong , Li Yun , Liao Duanping , Limacher Marian C. , Lin Henry J. , Lindgren Cecilia M. , Lubitz Steven A. , Mahajan Anubha , McKnight Barbara , zu Schwabedissen Henriette Meyer , Milaneschi Yuri , Mononen Nina , Morris Andrew P. , Nalls Mike A. , Navis Gerjan , Neijts Melanie , Nikus Kjell , North Kari E. , O'Connor Daniel T. , Ormel Johan , Perz Siegfried , Peters Annette , Psaty Bruce M. , Raitakari Olli T. , Risbrough Victoria B. , Sinner Moritz F. , Siscovick David , Smit Johannes H. , Smith Nicholas L. , Soliman Elsayed Z. , Sotoodehnia Nona , Staessen Jan A. , Stein Phyllis K. , Stilp Adrienne M. , Stolarz-Skrzypek Katarzyna , Strauch Konstantin , Sundström Johan , Swenne Cees A. , Syvänen Ann-Christine , Tardif Jean-Claude , Taylor Kent D. , Teumer Alexander , Thornton Timothy A. , Tinker Lesley E. , Uitterlinden André G. , van Setten Jessica , Voss Andreas , Waldenberger Melanie , Wilhelmsen Kirk C. , Willemsen Gonneke , Wong Quenna , Zhang Zhu-Ming , Zonderman Alan B. , Cusi Daniele , Evans Michele K. , Greiser Halina K. , van der Harst Pim , Hassan Mohammad , Ingelsson Erik , Järvelin Marjo-Riitta , Kääb Stefan , Kähönen Mika , Kivimaki Mika , Kooperberg Charles , Kuh Diana , Lehtimäki Terho , Lind Lars , Nievergelt Caroline M. , O'Donnell Chris J. , Oldehinkel Albertine J. , Penninx Brenda , Reiner Alexander P. , Riese Harriëtte , van Roon Arie M. , Rioux John D. , Rotter Jerome I. , Sofer Tamar , Stricker Bruno H. , Tiemeier Henning , Vrijkotte Tanja G. M. , Asselbergs Folkert W. , Brundel Bianca J. J. M. , Heckbert Susan R. , Whitsel Eric A. , den Hoed Marcel , Snieder Harold , de Geus Eco J. C. 
Published: June 2017

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.