Genetic loci associated with heart rate variability and their effects on cardiac disease risk

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

doi:10.1038/ncomms15805

Abstract

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.

Highlights

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality
These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants in proteins (RGS6, GNG11) known to influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization
In data from up to 11,234 Hispanic/Latino individuals, five single-nucleotide polymorphism (SNPs) in five of the eight loci identified for RMSSD, seven SNPs in six of the seven loci for SDNN and three SNPs in three of the five loci for pvRSA/HF showed a statistically significant association that was consistent in direction with the association in individuals of European ancestry (Table 4)

Summary

Introduction

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. To improve our understanding of the genetic basis of HRV, we performed a two-stage meta-analysis of genome-wide association studies (GWAS) in up to 53,174 individuals of European ancestry on three HRV traits (the s.d. of the normal-to-normal inter beat intervals (SDNN), the root mean square of the successive differences of inter beat intervals (RMSSD) and the peak-valley respiratory sinus arrhythmia or high frequency power (pvRSA/HF)) These HRV traits were measured during resting, basal recordings ranging in length from ultrashort 10-s electrocardiograms (ECGs) to up to 90 min of sitting or from 2 to 12 h of daytime recording. We detect 17 SNPs in eight loci harbouring several genes preferentially expressed in the sinoatrial node and significant negative genetic correlations of HRV with heart rate and blood pressure These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants in proteins (RGS6, GNG11) known to influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization

Methods

Results

Conclusion