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

Ilja Maria NolteM Loretto MunozVinicius TraganteAzmeraw T Amare Rick Jansen Ahmad VaezBenedikt von der HeydeChristy L AveryJoshua C BisBram DierckxJenny van DongenStephanie M GogartenPhilippe GoyetteJussi HernesniemiVille HuikariShih-Jen HwangDeepali JajuKathleen F KerrAlexander KluttigBouwe P KrijtheJitender KumarSander W van der LaanLeo-Pekka LyytikäinenAdam X MaihoferArpi MinassianPeter J van der MostMartina Müller-NurasyidMichel G Nivard Mirna AndelicJames D StewartJulian F ThayerNiek Verweij Andrew WongDelilah ZabanehMohammad H ZafarmandAbdel AbdellaouiSulayma AlbarwaniChristine AlbertAlvaro AlonsoForam AsharJuha AuvinenTomas AxelssonDewleen G BakerPaul I W de BakkerMatteo BarcellaRiad BayoumiRob J BieringaDorret BoomsmaGabrielle BoucherAnnie R BrittonIngrid ChristophersenAndrea DietrichGeorge B EhretPatrick T EllinorMarkku EskolaJanine F FelixJohn S FlorasOscar H FrancoPeter FribergMaaike G J GademanMark A GeyerVilmantas GiedraitisCatharina A HartmanDaiane HemerichAlbert HofmanJouke-Jan HottengaHeikki HuikuriNina Hutri-KähönenXavier JouvenJuhani JunttilaMarkus JuonalaAntti M KiviniemiJan A KorsMeena KumariTatiana KuznetsovaCathy C LaurieJoop D LefrandtYong LiYun LiDuanping LiaoMarian C LimacherHenry J LinCecilia M LindgrenSteven A LubitzAnubha MahajanBarbara McKnightHenriette Meyer Zu SchwabedissenYuri MilaneschiNina MononenAndrew P MorrisMike A NallsGerjan NavisMelanie NeijtsKjell NikusKari E NorthDaniel T O'ConnorJohan OrmelSiegfried PerzAnnette PetersBruce M PsatyOlli T RaitakariVictoria B RisbroughMoritz F SinnerDavid SiscovickJohannes H SmitNicholas L SmithElsayed Z SolimanNona SotoodehniaJan A StaessenPhyllis K SteinAdrienne M StilpKatarzyna Stolarz-SkrzypekKonstantin StrauchJohan SundströmCees A SwenneAnn-Christine SyvänenJean-Claude TardifKent D TaylorAlexander TeumerTimothy A ThorntonLesley E TinkerAndré G UitterlindenJessica van SettenAndreas VossMelanie WaldenbergerKirk C WilhelmsenGonneke WillemsenQuenna WongZhu-Ming ZhangAlan B ZondermanDaniele CusiMichele K EvansHalina K GreiserPim van der HarstMohammad HassanErik IngelssonMarjo-Riitta JärvelinStefan KääbMika KähönenMika KivimakiCharles KooperbergDiana KuhTerho LehtimäkiLars LindCaroline M NievergeltChris J O'DonnellAlbertine J OldehinkelBrenda PenninxAlexander P ReinerHarriëtte RieseArie M van RoonJohn D RiouxJerome I RotterTamar SoferBruno H StrickerHenning TiemeierTanja G M VrijkotteFolkert W. AsselbergsBianca J J M BrundelSusan R HeckbertEric A WhitselMarcel den HoedHarold SniederEco J C de Geus

Published in: Nature communications (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.