Variant2Celltype: An Integrative Framework for Mapping Cardiometabolic Genetic Variants to Cell-Type-Specific Regulatory Regions

Identification of cell-type-specific genetic risk variants is crucial to unraveling the molecular mechanisms of complex diseases. Genome-wide association studies (GWAS) have identified thousands of risk loci associated with cardiometabolic conditions such as type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). However, cell type-specific regulatory roles of these variants remain largely unknown. To address this, we developed Variant2Celltype ( https://www.swainasish.in/variant2celltype ), an integrative framework that systematically links GWAS variants to their regulatory cell types using single-cell ATAC-seq data derived from two functional genomic datasets: peripheral blood mononuclear cells (PBMCs) and heart tissue. Using a chromatin accessibility-based, window-level mapping strategy, Variant2Celltype identifies variants overlapping cell type-specific regulatory regions associated with cardiometabolic disease. Thus, it reveals that T2DM- and CVD-associated variants are significantly enriched in monocytes, cardiac fibroblasts, and cardiomyocytes. Notably, the LPL and MRAS loci showed chromatin accessibility across both immune and cardiac cell types, and these genes were implicated in biological pathways related to lipid metabolism, vascular inflammation, and cardiac remodeling. Variant2Celltype offers an integrative resource for uncovering cell-type-specific regulatory mechanisms underlying cardiometabolic diseases.