Unfolding the genotype-to-phenotype black box of cardiovascular diseases through cross-scale modeling

Summary: Complex traits such as cardiovascular diseases (CVD) are the results of complicated processes jointly affected by genetic and environmental factors. Genome-wide association studies (GWAS) identified genetic variants associated with diseases but usually did not reveal the underlying mechanisms. There could be many intermediate steps at epigenetic, transcriptomic, and cellular scales inside the black box of genotype-phenotype associations. In this article, we present a machine-learning-based cross-scale framework GRPath to decipher putative causal paths (pcPaths) from genetic variants to disease phenotypes by integrating multiple omics data. Applying GRPath on CVD, we identified 646 and 549 pcPaths linking putative causal regions, variants, and gene expressions in specific cell types for two types of heart failure, respectively. The findings suggest new understandings of coronary heart disease. Our work promoted the modeling of tissue- and cell type-specific cross-scale regulation to uncover mechanisms behind disease-associated variants, and provided new findings on the molecular mechanisms of CVD.