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Dilated Cardiomyopathy Risk Loci, Polygenic Score Emerge From Heart Imaging GWAS

NEW YORK – Starting from heart imaging measurements, a team led by investigators at Massachusetts General Hospital and the Broad Institute has identified dozens of genetic loci linked to cardiac structure changes that lie behind the heart condition dilated cardiomyopathy.

By tapping into magnetic resonance imaging (MRI)-based cardiac structure data for more than 36,000 individuals from the UK Biobank, the researchers performed a genome-wide association study focused on variants that corresponded with dilated cardiomyopathy-related changes affecting features of the heart's left ventricle. Their findings, published in Nature Communications on Friday, highlighted SNPs at 45 previously unappreciated risk loci, including variants near genes such as TTN that have been implicated in Mendelian cardiomyopathy conditions in the past.

"[O]ur results provide new insights into the role that common genetic variants play in determining the structure and function of the heart, even in the context of rare, high-impact mutations in cardiomyopathy-related genes," senior author Krishna Aragam, a cardiology, genomic medicine, and medical and population genetics researcher affiliated with MGH, the Broad Institute, and Harvard Medical School, and his colleagues wrote.

The team delved into the collection of common variants implicated in a dilated cardiomyopathy-related trait that could be measured by MRI — known as "left ventricular end systolic volume" — to narrow in on a 28-SNP polygenic risk score that showed promise for finding those at risk of the heart muscle condition, which can progress to heart failure and often requires a heart transplant.

In the initial stage of the GWAS, the researchers searched for variants contributing to dilated cardiomyopathy-associated heart structure features in 36,041 UK Biobank participants with available array-based genotyping profiles and cardiac MRI-based heart measurements, uncovering variants with ties to one or more heart features at 57 new and known genetic loci.

When the team tested more than 100 of those candidate SNPs in 2,184 individuals from the Multi-Ethnic Study of Atherosclerosis, it saw similar associations involving 99 of the variants, while a few dozen of the SNPs appeared to have the same directionality in summary GWAS data for some 19,999 participants in the BioBank Japan study.

The investigators then dug into the cardiomyopathy-related genes using a complementary transcriptome-wide association study and went on to search for polygenic scores relevant to dilated cardiomyopathy risk with the help of a phenome-wide association study that included information for hundreds of thousands UK Biobank participants.

In particular, the team found that a polygenic score reflecting left ventricular end systolic volume appeared to most closely track with dilated cardiomyopathy risk, independent of the effects associated with mutations affecting the Mendelian risk gene TTN.

"These findings emphasize the potential scope and impact of common genetic variants on cardiac structure and function, and suggest that the penetrance of high-impact rare variants may be influenced by carriers' polygenic backgrounds," the authors wrote, noting that "future studies will be required to confirm these observations, and to ascertain whether these individuals might be protected from cardiomyopathy."

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