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Resting Heart Rate Linked to Overall Mortality Through Dozens of Genetic Loci

NEW YORK (GenomeWeb) – A team led by researchers at the University Medical Center Groningen has linked some five dozen loci to resting heart rate.

A person's resting heart rate is a known predictor of overall mortality, as people with higher resting heart rates are at increased risk of death. As they reported in Nature Genetics today, the researchers performed a genome-wide association study that linked more than 60 loci to resting heart rate. The researchers then used these loci to explore this connection between resting heart rate and mortality, and estimated that a genetically predicted increase in heart rate of five beats per minute leads to a reduction in life expectancy of 2.9 years for mean and 2.6 years for women.

"Our findings provide evidence for shared genetic predictors of resting heart rate and all-cause mortality," Groningen's Pim van der Harst and his colleagues wrote in their paper.

The team performed a GWAS that drew upon 134,251 people from the UK Biobank. The cohort had an average age of 56.6 years, and experienced 2,364 mortality events during a mean 4.9 years of follow-up.

Through their GWAS, the researchers uncovered 76 loci linked to resting heart rate, though only 64 could be replicated in a cohort of 130,795 people. Of these, the researchers noted that 46 loci had not been linked before to resting heart rate. In addition, they uncovered evidence of multiple associations with resting heart rate at 11 of these loci.

The researchers noted, however, that the magnitude of these associations was small. They ranged from 0.2 beats to 1.1 beats per minute per effect allele and explained a total of 2.5 percent of variance in resting heart rate.

Van der Harst and his colleagues also devised a weighted genetic risk score based on the number of alleles that increased resting heart rate and their association strength. They found that genetically determined higher resting heart rate was associated with higher body mass index, blood pressure, and supraventricular tachycardia, among other traits.

They likewise uncovered an association between genetic variants associated with resting heart rate and all-cause mortality. They estimated that these variants lead to a 20 percent increase in all-cause mortality risk for every five beat per minute increase in resting heart rate. This, they added, means that there's a decrease of between 1.9 years and 4.1 years in life expectancy for every increase of five beats per minute in resting heart rate in men, and a decrease of between 1.8 years and 3.7 years in life expectancy for women.

The researchers also examined whether these loci included ones linked to cardiac phenotypes. They prioritized 102 candidate genes located near these 64 loci and by searching through Online Mendelian Inheritance in Man, they found that some of these genes have been linked to cardiomyopathies, long QT syndrome, and congenital heart disease. An analysis using the DEPICT tool uncovered 622 significantly enriched gene sets, which the researchers then clustered to find 74 gene sets with relevance to cardiac biology.

This suggested to van der Harst and his colleagues that the association between resting heart rate and mortality is likely due to shared biology, such as basic cell biology behind heart rate and susceptibility to arrhythmias.

"The loci identified as influencing resting heart rate are also implicated in overall mortality (and, consequently, life expectancy) and therefore warrant further research into the underlying mechanisms," the researchers wrote.

The researchers also cautioned that no such mechanisms have yet been proven to link any of the loci they identified to mortality or heart rate.