Identification of genomic loci associated with resting heart rate and shared genetic predictors with all-cause mortality

Eppinga, Ruben N.; Hagemeijer, Yanick; Burgess, Stephen; Hinds, David A.; Stefánsson, Kári; Guðbjartsson, Daníel F.; Veldhuisen, Dirk J. van; Munroe, Patricia B.; Verweij, Niek; Harst, Pim van der

doi:10.1038/ng.3708

Cited by 141 publications

(156 citation statements)

References 39 publications

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“…Elevated RHR may also reflect underlying arrhythmias, which increase mortality risk 32. Although RHR has been thought to be a silent bystander,33 a recent genome-wide association study has confirmed the causal role of genetically determined RHR in mortality,34 which found relative risks larger than those of our study. Few data exist exploring the association between RHR and the risk of cancer.…”

Section: Discussioncontrasting

confidence: 47%

Resting heart rate, temporal changes in resting heart rate, and overall and cause-specific mortality

Seviiri

Lynch

Hodge

et al. 2017

Heart

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Section: Discussioncontrasting

confidence: 47%

Resting heart rate, temporal changes in resting heart rate, and overall and cause-specific mortality

Seviiri

Lynch

Hodge

et al. 2017

Heart

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“…In a large GWAS, combining 46 loci associated with RHR, only 2.5% of the variance of RHR was explained 1. Here, a genetically predicted RHR increase of 5 bpm increased the risk of mortality by 20%.…”

Section: Discussionmentioning

confidence: 79%

“…Genome-wide association studies (GWAS) have so far found several genetic loci that are significantly associated with RHR. However, when combining the GWAS identified heart rate-increasing alleles, only a few percentages of the variance in heart rate is explained 1. Using the classical twin design, the relative contribution of genetic and environmental factors can be determined.…”

Section: Introductionmentioning

confidence: 99%

Heritability of resting heart rate and association with mortality in middle-aged and elderly twins

Jensen

Wod

Galatius

et al. 2017

Heart

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Objective Resting heart rate (RHR) possibly has a hereditary component and is associated with longevity. We used the classical biometric twin study design to investigate the heritability of RHR in a population of middle-aged and elderly twins and, furthermore, studied the association between RHR and mortality. Methods In total, 4282 twins without cardiovascular disease were included from the Danish Twin Registry, hereof 1233 twin pairs and 1816 ’single twins’ (twins with a non-participating co-twin); mean age 61.7 (SD 11.1) years; 1334 (31.2%) twins died during median 16.3 (IQR 13.8–16.5) years of follow-up assessed through Danish national registers. RHR was assessed by palpating radial pulse. Results Within pair correlations for RHR adjusted for sex and age were 0.23 (95% CI 0.14 to 0.32) and 0.10 (0.03 to 0.17) for RHR in monozygotic (MZ) and dizygotic (DZ) twin pairs, respectively. Overall, heritability estimates were 0.23 (95% CI 0.15 to 0.30); 0.27 (0.15 to 0.38) for males and 0.17 (0.06 to 0.28) for females. In multivariable models adjusting for age, gender, body mass index, diabetes, hypertension, pulmonary function, smoking, physical activity and zygosity, RHR was significantly associated with mortality (eg, RHR >90 vs 61–70 beats per min: all-cause HR 1.56 (95% CI 1.21 to 2.03); cardiovascular 2.19 (1.30 to 3.67). Intrapair twin comparison revealed that the twin with the higher RHR was significantly more likely to die first and the probability increased with increase in intrapair difference in RHR. Conclusions RHR is a trait with a genetic influence in middle-aged and elderly twins free of cardiovascular disease. RHR is independently associated with longevity even when familial factors are controlled for in a twin design.

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“…This finding, that mortality selection may lead to attenuation, has also been observed in the context of Mendelian randomization. 5,6 If certain genetic profiles are associated with increased risks for mortality, 38,39 then individuals with such genotypes are less likely to be observed in older samples (e.g. Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Mortality Selection in a Genetic Sample and Implications for Association Studies

Domingue

Belsky²,

Harrati

et al. 2016

Preprint

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Background: Mortality selection occurs when a non-random subset of a population of interest has died before data collection and is unobserved in the data. Mortality selection is of general concern in the social and health sciences, but has received little attention in genetic epidemiology. We tested the hypothesis that mortality selection may bias genetic association estimates, using data from the US-based Health and Retirement Study (HRS). Methods: We tested mortality selection into the HRS genetic database by comparing HRS respondents who survive until genetic data collection in 2006 with those who do not. We next modelled mortality selection on demographic, health and social characteristics to calculate mortality selection probability weights. We analysed polygenic score associations with several traits before and after applying inverse-probability weighting to account for mortality selection. We tested simple associations and time-varying genetic associations (i.e. gene-by-cohort interactions). Results: We observed mortality selection into the HRS genetic database on demographic, health and social characteristics. Correction for mortality selection using inverse probability weighting methods did not change simple association estimates. However, using these methods did change estimates of gene-by-cohort interaction effects. Correction for mortality selection changed gene-by-cohort interaction estimates in the opposite direction from increased mortality selection based on analysis of HRS respondents surviving through 2012.

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Identification of genomic loci associated with resting heart rate and shared genetic predictors with all-cause mortality

Cited by 141 publications

References 39 publications

Resting heart rate, temporal changes in resting heart rate, and overall and cause-specific mortality

Resting heart rate, temporal changes in resting heart rate, and overall and cause-specific mortality

Heritability of resting heart rate and association with mortality in middle-aged and elderly twins

Mortality Selection in a Genetic Sample and Implications for Association Studies

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