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Scientists Use Cell State Data to Build Improved Polygenic Risk Score for Coronary Artery Disease

A hybrid polygenic risk score for coronary artery disease (CAD) built using data on newly identified disease-associated cell states is reported in the American Journal of Human Genetics this week. A person's risk of CAD is determined by an interplay of genetic and environmental factors, and much progress has been made in linking regions of the genome to disease risk. Still, it remains challenging to identify causal genes underlying genetic associations and the cell types through which the effect is mediated. In this week's study, a group led by scientists from the University of Eastern Finland performed single-cell RNA sequencing on thoracic aortas of healthy and atherosclerotic mice, uncovering 12 cell states that increase as the disease progresses. They then validated their findings in separate mouse experiments and in samples from human with atherosclerosis, identifying common pathways, transcription factors, and ligands that define the cell state changes. They linked their findings to genome-wide association studies to prioritize the relevance of atherosclerosis-associated cell states in the biology and heritability of CAD, using the results to create the hybrid PRS with superior performance to a classical PRS. The work, the authors write, provides an "in-depth characterization of atherosclerosis-associated cell states and demonstrate[s] the value of cell-state-specific markers in understanding the genetic basis of CAD."