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Heart Rate GWAS Provides Insight on Exercise Response, Recovery

NEW YORK (GenomeWeb) – A genome-wide association study has implicated genes involved in neuron- and autonomous nervous system-related pathways in individuals' heart rate (HR) response to exercise and recovery afterwards.

The work "adds a new line of evidence to the theory that components of the autonomous nervous system are underlying inter-individual differences in HR recovery," senior author Pim van der Harst, a cardiology and genetics researcher affiliate with the University of Groningen and the Netherlands Heart Institute, and his colleagues wrote.

A team led by investigators at the University of Groningen in the Netherlands considered genotyping profiles for more than 58,800 UK Biobank participants, searching for genetic loci with ties to exercise-related HR increases and post-exercise HR recovery. The GWAS, appearing online today in Nature Communications, led to HR-associated variants at 23 loci in and around three-dozen candidate genes from pathways involved in neuronal function and activity in the parasympathetic and sympathetic branches of the autonomic nervous system.

Consistent with prior studies, the team saw signs that HR recovery involves a dip in sympathetic nervous system activity and parasympathetic reactivation, for example. On the other hand, the group did not see any clear associations between the HR-associated loci and other heart-related features such as cardiovascular disease or mortality risk.

Features such as peak HR during exercise and HR recovery after exercise have previously been proposed as markers for risk of heart failure, cardiac death, and other conditions, the authors explained. But while some HR mediators have been untangled already, they noted that "the exact molecular mechanisms underlying inter-individual differences in HR response to exercise, as defined by HR increase and HR recovery, are unknown."

To dig into those mechanisms, the researchers started from data for 96,600 individuals enrolled in the UK Biobank, focusing in on 58,818 genotyped participants with one or more cardiac assessments.

Together with data on individuals' cardiac assessments — electrocardiogram measurements taken before, during, and after a six-minute stint on stationary bike at 30 percent or 50 percent of an individual's maximum workload — they considered directly genotyped and imputed SNPs from Affymetrix (Thermo Fisher Scientific) array-based profiles.

The search led to 25 variants with genome-wide significant associations with HR increase or recovery, falling at 23 loci in or near 36 candidate genes. The team whittled the gene set down based on associated SNP patterns, expression quantitative trait locus profiles, and long-range interactions identified with the help of Hi-C chromatin crosslinking data.

Variants in some of the genes, such as TTN/CCDC141, appeared to have closer ties to resting heart rate, the researchers reported, while others were more closely associated with HR variability, exercise-related HR rises, or post-workout recovery.

Along with analyses of gene functions and pathways behind these associations, they subsequently considered polygenic scores for SNPs from the GWAS in relation to many more traits and conditions. Though these scores were not associated with conditions such as atrial fibrillation or coronary artery disease, the team did see potential ties to traits such as diastolic blood pressure and fathers' lifespan — associations that are yet to be explored in more detail.

"[W]hether or not the [latter] association is a true-positive one," the authors wrote, "it is possible to conclude from our results that HR response to exercise may not be as important for the human lifespan as other more established risk factors such as blood pressure, lipids, BMI, or educational attainment."

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