NEW YORK – New research by investigators at the University of Pennsylvania and elsewhere has revealed interactions between common and rare genetic variants contributing to heart failure, hinting that common polygenic variants may ultimately provide a more nuanced view of heart failure risk in the clinic.
"Together, these findings discern genetic links between dysregulated metabolism and heart failure and highlight a polygenic component to heart failure not captured by current clinical genetic testing," co-senior and corresponding author Michael Levin, a researcher affiliated with the University of Pennsylvania Perelman School of Medicine, and colleagues wrote in a paper published in Nature Genetics on Monday.
For their study, Levin and his colleagues brought together data for nearly 2.4 million individuals enrolled in eight research cohorts for a multipopulation genome-wide association study focused on finding common variants associated with heart failure. They also brought in exome or genome sequence data for more than 376,000 individuals to perform a parallel analysis of rare variants contributing to heart failure — a condition that has been linked to rare, damaging alterations in TTN and several other genes.
The team's GWAS analyses — which included nearly 1.9 million European participants, 257,928 participants of East Asian ancestry, 142,872 African ancestry individuals, and 63,835 individuals of admixed American ancestry — led to 176 common variants with genome-wide significant ties to heart failure, including 105 variants not linked to heart failure in the past.
With the help of gene prioritization, functional enrichment, and pleiotropic analyses, the investigators grouped the variants into five trait or disease modules based on their association with everything from immune activity or arrhythmia to atherosclerosis or lipid features; blood pressure or renal function; and anthropomorphic traits or obesity.
On the rare variant side, the team analyzed electronic health records, exome sequence, or genome sequence data for 376,334 participants with or without heart failure from three large research efforts: the Penn Medicine Biobank, the UK Biobank, and All of Us research project.
In the process, the researchers identified rare, loss-of-function alterations affecting known heart failure genes such as TTN, MYBPC3, FLNC, and BAG3 and saw an enrichment for rare heart failure-related variants in genes implicated in cardiomyopathy.
"This rare variant analysis provides important confirmation for the role of these established cardiomyopathy genes using a large genome-first population-based study design, which has different strengths compared with the ascertained cardiomyopathy cohorts and family studies that have been historically used to prioritize these genes," Levin explained in an email.
Using polygenic risk scores (PRS) assembled with their GWAS meta-analysis summary statistic data, meanwhile, the investigators found that heart failure risk can be stratified with common variants in a multipopulation PRS, even in individuals carrying TTN variants with established ties to heart failure.
"Individually, these common genetic variants have small influences on risk of heart failure, but we're beginning to explain a more significant portion of the heritability of heart failure," Levin said, noting that "aggregating the effects of common genetic variants, in the form of a polygenic score, we can begin to better explain genetic risk of heart failure."
"While this polygenic score isn't ready for clinical use," he emphasized, "this work suggests that in the future, we may need to consider a broader spectrum of genetic variation that includes both common and rare variants when we think about clinical risk of heart failure."
Building on their findings so far, members of the team plan to continue untangling the interplay between rare heart failure-linked variants and common, polygenic risk variants in their effort to understand genetic contributions to heart failure risk and inherited cardiomyopathies.
"Future studies are warranted to investigate the use of polygenic background to adjudicate cardiomyopathy genes with less certain levels of evidence and variants of unknown significance, as well as the role of PRS testing more broadly when assessing heart failure etiology and risk," the authors wrote.