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Meta-analysis, Animal Models Link 20 Genes to Heart Rate

NEW YORK (GenomeWeb News) – By combining a meta-analysis with follow-up experiments in two model systems, an international team of researchers uncovered 14 new loci associated with heart rate and homed in on 20 candidate genes, the team reported in an online article in Nature Genetics yesterday.

Resting heart rate is indicative of overall cardiac health, and a high heart rate has been linked to increased cardiovascular disease and death due to cardiac events as well as overall mortality. While previous studies have found a handful of loci associated with heart rate, the team of researchers led by Ruth Loos, from the Icahn School of Medicine at Mount Sinai in New York and the Medical Research Council Epidemiology Unit in Cambridge, UK, aimed to find additional variants by drawing on a large number of genome-wide association studies.

"Without any prior hypothesis, we studied the entire human genome hoping to identify new genetic variations that no one before had even imagined would play a role in the regulation of heart rate," Loos, the senior author of the study, said in a statement. "This discovery is just the beginning of something new and exciting and can hopefully be used to identify new drugs that can be used for the treatment of heart rhythm disorders."

Loos and her team gathered together genome-wide association study data from 36 previously conducted studies encompassing 85,787 people of European descent and 6,568 people of Indian ancestry. From their analysis of the association between more than 2.5 million SNPs and heart rate in those populations, the researchers identified 12 loci, including seven that had been described previously.

Two additional loci with secondary associations were identified through conditional analyses of the GWAS data.

The top SNPs from 42 loci, including those two additional loci, were selected for follow-up analysis by the researchers in 88,823 people of European descent from an additional 27 GWAS.

In a joint analysis of the results from the first and second stages of this meta-analysis, the researchers found 21 loci with associations to heart rate that reached statistical significance. Those 21 loci included the 12 loci they identified in the first stage — including the seven previously described loci — plus nine additional ones. "Hence, our study confirms the [seven] previously identified loci and identifies 14 new loci robustly associated with heart rate," Loos and her colleagues wrote.

Each loci, the researchers determined, has a small influence on heart rate, with an effect size ranging between 0.21 beats per minute to 0.74 beats per minute per effect allele. Added together, though, the loci could have a greater effect. In a population of adults with the highest genetic predisposition scores based on a summing of these loci compared to those with the lowest scores, there was a difference of 4.1 beats per minute. In children that difference was 4.9 beats per minute.

A number of the newly uncovered loci are also associated with electrophysiological heart functions. For example, five of the loci were associated with atrial fibrillation — three associated with increased risk and two associated with decreased risk. Little evidence was found, though, for associations with either blood pressure or coronary artery disease.

A database analysis using MAGENTA found that these loci were enriched on other cardiac-related pathways, such as those involved in the regulation of heart contractions and cardiomyopathies.

More than 230 genes are found within 500 kilobases of the 21 loci associated with heart rate, and, based on proteomic, eQTL, and in silico analyses, the researchers narrowed their focus to 49 candidate genes. Using two model systems — fruit flies and zebrafish — Loos and her team found additional support for 20 of those candidate genes to play a role in the regulation of heart rate.

They noted that the most convincing evidence they found was for orthologs of PLD1 and MFN1 — when they were downregulated in both models resting heart rate was reduced. Down-regulation of the PLD1 ortholog in zebrafish also was linked to an unlooped heart. In addition, downregulation of the MFN1 ortholog in flies was associated with an increased risk of arrhythmia. Other genes, including ACHE, PCOLCE, and FADS3, were also linked to arrhythmia in flies.

"Taken together, these results may enable the discovery of new druggable targets for the prevention and treatment of cardiovascular endpoints by selective reduction of heart rate and arrhythmia susceptibility," the researchers wrote.