NEW YORK – New research suggests that a polygenic risk score (PRS) can not only help in identifying individuals at risk of developing hypertrophic cardiomyopathy (HCM), a progressive heart condition marked by left ventricle changes that can lead to sudden cardiac death, but can also predict which HCM patients are prone to particularly severe forms of the disease.
"[T]his study identifies multiple clinical applications for a PGS in HCM, including in general population screening, stratification of rare variant carriers into higher and lower risk of penetrant HCM, and as a new risk predictor of adverse outcomes in individuals with HCM," co-senior and corresponding author James Ware, a researcher affiliated with Imperial College London, Imperial College Healthcare NHS Trust, Guy's and St. Thomas' NHS Foundation Trust, and the Broad Institute, and his colleagues wrote in Nature Genetics on Tuesday.
For their study, Ware and colleagues from the UK, the Netherlands, Canada, and elsewhere considered summary statistics and other data for 5,900 European ancestry individuals with HCM and nearly 63,400 unaffected control individuals from a prior genome-wide association study and GWAS meta-analysis.
They then combined those data with findings from a multitrait GWAS that spanned several HCM-related traits of phenotypes in more than 36,000 individuals to come up with PRSs for HCM and several genetically correlated traits such as magnetic resonance imaging-based left ventricular end-systolic volume and left ventricular circumferential strain to left ventricular concentricity.
"Although HCM has classically been considered a Mendelian disease, a causal rare variant is identified in only one-third of cases, with population studies highlighting the incomplete penetrance and variable expressivity of such variants," the authors explained, noting that recent GWAS have demonstrated that common variants contribute substantially to HCM risk.
Indeed, when the investigators tested an HCM PRS in hundreds of thousands of UK Biobank participants, along with participants from several clinical studies, they found that individuals who classified at high HCM risk with the polygenic score were more prone to HCM diagnoses or related phenotypes. The risk score also appeared to offer clues to the penetrance in individuals carrying rare, HCM-related pathogenic variants.
By considering PRS associations in individuals with the condition or their relatives, meanwhile, the team found that the scores could also provide predictions related to the severity of the condition or the advent of HCM-related adverse cardiovascular events such death or increased ventricular wall thickness.
"Findings from this study emphasize the importance of the polygenic contribution to HCM disease risk, classically considered a Mendelian disease caused by rare variants in sarcomere-encoding genes," the authors reported, adding that "the recognition of polygenic, rather than sarcomeric HCM, will be of diagnostic importance, with potential implications for clinical management, reproductive counseling, and family screening" in HCM patients.