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van de Vegte YJ, Eppinga RN, van der Ende MY, Hagemeijer YP, Mahendran Y, Salfati E, Smith AV, Tan VY, Arking DE, Ntalla I, Appel EV, Schurmann C, Brody JA, Rueedi R, Polasek O, Sveinbjornsson G, Lecoeur C, Ladenvall C, Zhao JH, Isaacs A, Wang L, Luan J, Hwang S, Mononen N, Auro K, Jackson AU, Bielak LF, Zeng L, Shah N, Nethander M, Campbell A, Rankinen T, Pechlivanis S, Qi L, Zhao W, Rizzi F, Tanaka T, Robino A, Cocca M, Lange L, Müller-Nurasyid M, Roselli C, Zhang W, Kleber ME, Guo X, Lin HJ, Pavani F, Galesloot TE, Noordam R, Milaneschi Y, Schraut KE, den Hoed M, Degenhardt F, Trompet S, van den Berg ME, Pistis G, Tham Y, Weiss S, Sim XS, Li HL, van der Most PJ, Nolte IM, Lyytikäinen L, Said MA, Witte DR, Iribarren C, Launer L, Ring SM, de Vries PS, Sever P, Linneberg A, Bottinger EP, Padmanabhan S, Psaty BM, Sotoodehnia N, Kolcic I, DCCT/EDIC Research Group , Arnar DO, Gudbjartsson DF, Holm H, Balkau B, Silva CT, Newton-Cheh CH, Nikus K, Salo P, Mohlke KL, Peyser PA, Schunkert H, Lorentzon M, Lahti J, Rao DC, Cornelis MC, Faul JD, Smith JA, Stolarz-Skrzypek K, Bandinelli S, Concas MP, Sinagra G, Meitinger T, Waldenberger M, Sinner MF, Strauch K, Delgado GE, Taylor KD, Yao J, Foco L, Melander O, de Graaf J, de Mutsert R, de Geus EJC, Johansson Å, Joshi PK, Lind L, Franke A, Macfarlane PW, Tarasov KV, Tan N, Felix SB, Tai E, Quek DQ, Snieder H, Ormel J, Ingelsson M, Lindgren C, Morris AP, Raitakari OT, Hansen T, Assimes T, Gudnason V, Timpson NJ, Morrison AC, Munroe PB, Strachan DP, Grarup N, Loos RJF, Heckbert SR, Vollenweider P, Hayward C, Stefansson K, Froguel P, Groop L, Wareham NJ, van Duijn CM, Feitosa MF, O'Donnell CJ, Kähönen M, Perola M, Boehnke M, Kardia SLR, Erdmann J, Palmer CNA, Ohlsson C, Porteous DJ, Eriksson JG, Bouchard C, Moebus S, Kraft P, Weir DR, Cusi D, Ferrucci L, Ulivi S, Girotto G, Correa A, Kääb S, Peters A, Chambers JC, Kooner JS, März W, Rotter JI, Hicks AA, Smith JG, Kiemeney LALM, Mook-Kanamori DO, Penninx BWJH, Gyllensten U, Wilson JF, Burgess S, Sundström J, Lieb W, Jukema JW, Eijgelsheim M, Lakatta ELM, Cheng C, Dörr M, Wong T, Sabanayagam C, Oldehinkel AJ, Riese H, Lehtimäki T, Verweij N, van der Harst P
Nat Commun 14 (1) 4646 [2023-08-02; online 2023-08-02]
Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
Clinical Genomics Gothenburg [Collaborative]
NGI Uppsala (SNP&SEQ Technology Platform) [Service]
National Genomics Infrastructure [Service]
PubMed 37532724
DOI 10.1038/s41467-023-39521-2
Crossref 10.1038/s41467-023-39521-2
pmc: PMC10397318
pii: 10.1038/s41467-023-39521-2