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

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

SUBMITTER: Nolte IM

PROVIDER: S-EPMC5474732 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Nolte Ilja M IM Munoz M Loretto ML Tragante Vinicius V Amare Azmeraw T AT Jansen Rick R Vaez Ahmad A von der Heyde Benedikt B Avery Christy L CL Bis Joshua C JC Dierckx Bram B van Dongen Jenny J Gogarten Stephanie M SM Goyette Philippe P Hernesniemi Jussi J Huikari Ville V Hwang Shih-Jen SJ Jaju Deepali D Kerr Kathleen F KF Kluttig Alexander A Krijthe Bouwe P BP Kumar Jitender J van der Laan Sander W SW Lyytikäinen Leo-Pekka LP Maihofer Adam X AX Minassian Arpi A van der Most Peter J PJ Müller-Nurasyid Martina M Nivard Michel M Salvi Erika E Stewart James D JD Thayer Julian F JF Verweij Niek N Wong Andrew A Zabaneh Delilah D Zafarmand Mohammad H MH Abdellaoui Abdel A Albarwani Sulayma S Albert Christine C Alonso Alvaro A Ashar Foram F Auvinen Juha J Axelsson Tomas T Baker Dewleen G DG de Bakker Paul I W PIW Barcella Matteo M Bayoumi Riad R Bieringa Rob J RJ Boomsma Dorret D Boucher Gabrielle G Britton Annie R AR Christophersen Ingrid I Dietrich Andrea A Ehret George B GB Ellinor Patrick T PT Eskola Markku M Felix Janine F JF Floras John S JS Franco Oscar H OH Friberg Peter P Gademan Maaike G J MGJ Geyer Mark A MA Giedraitis Vilmantas V Hartman Catharina A CA Hemerich Daiane D Hofman Albert A Hottenga Jouke-Jan JJ Huikuri Heikki H Hutri-Kähönen Nina N Jouven Xavier X Junttila Juhani J Juonala Markus M Kiviniemi Antti M AM Kors Jan A JA Kumari Meena M Kuznetsova Tatiana T Laurie Cathy C CC Lefrandt Joop D JD Li Yong Y Li Yun Y Liao Duanping D Limacher Marian C MC Lin Henry J HJ Lindgren Cecilia M CM Lubitz Steven A SA Mahajan Anubha A McKnight Barbara B Zu Schwabedissen Henriette Meyer HM Milaneschi Yuri Y Mononen Nina N Morris Andrew P AP Nalls Mike A MA Navis Gerjan G Neijts Melanie M Nikus Kjell K North Kari E KE O'Connor Daniel T DT Ormel Johan J Perz Siegfried S Peters Annette A Psaty Bruce M BM Raitakari Olli T OT Risbrough Victoria B VB Sinner Moritz F MF Siscovick David D Smit Johannes H JH Smith Nicholas L NL Soliman Elsayed Z EZ Sotoodehnia Nona N Staessen Jan A JA Stein Phyllis K PK Stilp Adrienne M AM Stolarz-Skrzypek Katarzyna K Strauch Konstantin K Sundström Johan J Swenne Cees A CA Syvänen Ann-Christine AC Tardif Jean-Claude JC Taylor Kent D KD Teumer Alexander A Thornton Timothy A TA Tinker Lesley E LE Uitterlinden André G AG van Setten Jessica J Voss Andreas A Waldenberger Melanie M Wilhelmsen Kirk C KC Willemsen Gonneke G Wong Quenna Q Zhang Zhu-Ming ZM Zonderman Alan B AB Cusi Daniele D Evans Michele K MK Greiser Halina K HK van der Harst Pim P Hassan Mohammad M Ingelsson Erik E Järvelin Marjo-Riitta MR Kääb Stefan S Kähönen Mika M Kivimaki Mika M Kooperberg Charles C Kuh Diana D Lehtimäki Terho T Lind Lars L Nievergelt Caroline M CM O'Donnell Chris J CJ Oldehinkel Albertine J AJ Penninx Brenda B Reiner Alexander P AP Riese Harriëtte H van Roon Arie M AM Rioux John D JD Rotter Jerome I JI Sofer Tamar T Stricker Bruno H BH Tiemeier Henning H Vrijkotte Tanja G M TGM Asselbergs Folkert W FW Brundel Bianca J J M BJJM Heckbert Susan R SR Whitsel Eric A EA den Hoed Marcel M Snieder Harold H de Geus Eco J C EJC

Nature communications 20170614

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 p ...[more]

PMID: 28613276

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Project description:Heart rate variability (HRV) is the variation of cardiac inter-beat intervals over time resulting largely from the interplay between the sympathetic and parasympathetic branches of the autonomic nervous system. Individual differences in HRV are associated with emotion regulation, personality, psychopathology, cardiovascular health, and mortality. Previous studies have shown significant heritability of HRV measures. Here we extend genetic research on HRV by investigating sex differences in genetic underpinnings of HRV, the degree of genetic overlap among different measurement domains of HRV, and phenotypic and genetic relationships between HRV and the resting heart rate (HR). We performed electrocardiogram (ECG) recordings in a large population-representative sample of young adult twins (n=1060 individuals) and computed HRV measures from three domains: time, frequency, and nonlinear dynamics. Genetic and environmental influences on HRV measures were estimated using linear structural equation modeling of twin data. The results showed that variability of HRV and HR measures can be accounted for by additive genetic and non-shared environmental influences (AE model), with no evidence for significant shared environmental effects. Heritability estimates ranged from 47 to 64%, with little difference across HRV measurement domains. Genetic influences did not differ between genders for most variables except the square root of the mean squared differences between successive R-R intervals (RMSSD, higher heritability in males) and the ratio of low to high frequency power (LF/HF, distinct genetic factors operating in males and females). The results indicate high phenotypic and especially genetic correlations between HRV measures from different domains, suggesting that >90% of genetic influences are shared across measures. Finally, about 40% of genetic variance in HRV was shared with HR. In conclusion, both HR and HRV measures are highly heritable traits in the general population of young adults, with high degree of genetic overlap across different measurement domains.

Project description:ContextPlasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain.ObjectiveTo investigate association of genetic loci with CRP levels and risk of coronary heart disease.Design, setting, and participantsWe first carried out a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls.Main outcome measureRisk of coronary heart disease.ResultsPolymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (-14.8%; 95% confidence interval [CI], -17.6% to -12.0%; P = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, -3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease.ConclusionThe lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.

Project description:IntroductionStrict lockdown rules were imposed to the French population from 17 March to 11 May 2020, which may result in limited possibilities of physical activity, modified psychological and health states. This report is focused on HRV parameters kinetics before, during and after this lockdown period.Methods95 participants were included in this study (27 women, 68 men, 37 ± 11 years, 176 ± 8 cm, 71 ± 12 kg), who underwent regular orthostatic tests (a 5-minute supine followed by a 5-minute standing recording of heart rate (HR)) on a regular basis before (BSL), during (CFN) and after (RCV) the lockdown. HR, power in low- and high-frequency bands (LF, HF, respectively) and root mean square of the successive differences (RMSSD) were computed for each orthostatic test, and for each position. Subjective well-being was assessed on a 0-10 visual analogic scale (VAS). The participants were split in two groups, those who reported an improved well-being (WB+, increase >2 in VAS score) and those who did not (WB-) during CFN.ResultsOut of the 95 participants, 19 were classified WB+ and 76 WB-. There was an increase in HR and a decrease in RMSSD when measured supine in CFN and RCV, compared to BSL in WB-, whilst opposite results were found in WB+ (i.e. decrease in HR and increase in RMSSD in CFN and RCV; increase in LF and HF in RCV). When pooling data of the three phases, there were significant correlations between VAS and HR, RMSSD, HF, respectively, in the supine position; the higher the VAS score (i.e., subjective well-being), the higher the RMSSD and HF and the lower the HR. In standing position, HRV parameters were not modified during CFN but RMSSD was correlated to VAS.ConclusionOur results suggest that the strict COVID-19 lockdown likely had opposite effects on French population as 20% of participants improved parasympathetic activation (RMSSD, HF) and rated positively this period, whilst 80% showed altered responses and deteriorated well-being. The changes in HRV parameters during and after the lockdown period were in line with subjective well-being responses. The observed recordings may reflect a large variety of responses (anxiety, anticipatory stress, change on physical activity…) beyond the scope of the present study. However, these results confirmed the usefulness of HRV as a non-invasive means for monitoring well-being and health in this population.

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

Publications

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

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