A new polygenic risk score (PRS) derived from large multi-ancestry databases improves prediction of risk for developing the inherited genetic heart condition hypertrophic cardiomyopathy.
The results of the research, published in Nature Cardiovascular Research, show that penetrance of hypertrophic cardiomyopathy among carriers of known harmful sarcomere-gene variants is strongly modified by the accumulated effect of many common genetic variants.
This type of cardiomyopathy affects around one in 500 people in the U.S. and is mostly inherited. It causes the wall of the left ventricle, the heart’s main chamber for pumping blood around the body, to become abnormally thick and stiff, which can impair filling, obstruct blood leaving the heart, or trigger rhythm disturbances.
“Hypertrophic cardiomyopathy has traditionally been considered a Mendelian disease driven by pathogenic or likely pathogenic variants in sarcomere-encoding genes,” write lead author Pankaj Arora, MD, a professor at the University of Alabama at Birmingham, and colleagues.
While the condition is mostly passed on in an autosomal dominant fashion, not everyone who inherits a disease-linked mutation goes on to develop it. “These variants explain only one-third of cases, and variable penetrance suggests additional polygenic contributions,” write the authors.
Arora and colleagues created a PRS based on how many common DNA variants a person has that are linked to hypertrophic cardiomyopathy. They combined hypertrophic cardiomyopathy genetic-association data from seven mainly European case–control cohorts, the U.S. Million Veteran Program and BioBank Japan, with a view to producing a score that would transfer better across different ancestry groups than earlier, European-focused versions.
They applied the score to 258,361 adults in the All of Us Research Program, which includes people from diverse ethnic backgrounds, including 1,017 people with hypertrophic cardiomyopathy. They tested whether the PRS was associated with prevalence and age-related incidence of this condition in the general population, in people carrying known pathogenic or likely pathogenic variants in sarcomere genes and in people with sarcomere variants of uncertain significance.
In the overall cohort, prevalence of hypertrophic cardiomyopathy rose from 0.27% in the lowest fifth of scores to 0.60% in the highest fifth. The effect was stronger among carriers of recognized harmful sarcomere genetic variants. In this group, prevalence of the condition rose from 4.7% among those in the lowest fifth of polygenic risk scores to 15.1% among those in the highest.
In a separate analysis modelling the likelihood of developing hypertrophic cardiomyopathy over time, carriers with a high PRS had a 69-fold higher relative risk than non-carriers with a low PRS.
Among carriers of genetic variants of unknown significance, which may or may not be linked to the disease, hypertrophic cardiomyopathy prevalence was 1.05% in the group with the highest PRS and 0.39% in the lowest. The PRS performed well across ancestry groups, though performance was still weaker or uncertain in some non-European groups.
“This study contributes to the growing body of evidence supporting that common genetic variants contribute meaningfully to the risk of development of hypertrophic cardiomyopathy,” conclude the authors.
“Common variant burden substantially modifies disease prevalence and incidence, and [this study] supports the development of unified risk assessment models combining clinical risk factors and rare and common genetic variants.”
