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These variants influence gene expression by disrupting cis-regulatory elements (CREs), whose spatial and cell-type specificity are not adequately captured by conventional tools like multi-marker analysis of genomic annotation. Current methods either rely on linear proximity to genes or quantitative trait locus (QTL) data yet fail to integrate single-cell epigenomic information for a comprehensive annotation. Results: We present SC-VAR, a novel computational tool designed to enhance the interpretation of disease-associated risks from GWAS using single-cell epigenomic data. SC-VAR leverages single-cell epigenomic data to predict functional outcomes including risk genes, pathways, and cell types for both coding and noncoding disease-associated variants. We demonstrate that SC-VAR outperforms state-of-the-art methods by predicting more validated disease-related genes and pathways for multiple diseases. Additionally, SC-VAR identifies cell types that are susceptible to disease, along with their specific CREs and target genes linked to risk. By capturing a broad range of disease risks across human tissues at distinct developmental stages, SC-VAR could enhance our understanding of disease mechanisms in complex tissues across different life stages.<\/jats:p>","DOI":"10.1093\/bib\/bbaf123","type":"journal-article","created":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T04:36:47Z","timestamp":1743223007000},"source":"Crossref","is-referenced-by-count":1,"title":["SC-VAR: a computational tool for interpreting polygenic disease risks using single-cell epigenomic data"],"prefix":"10.1093","volume":"26","author":[{"given":"Gefei","family":"Zhao","sequence":"first","affiliation":[{"name":"Institute of Medical Technology, Peking University Health Science Center , 38 Xueyuan Rd, Hai Dian Qu, Beijing 100191 ,","place":["China"]},{"name":"Biomedical Engineering Department, Institute of Advanced Clinical Medicine, Peking University , 5 Yiheyuan Rd, Haidian District, Beijing 100191 ,","place":["China"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2831-2677","authenticated-orcid":false,"given":"Binbin","family":"Lai","sequence":"additional","affiliation":[{"name":"Institute of Medical Technology, Peking University Health Science Center , 38 Xueyuan Rd, Hai Dian Qu, Beijing 100191 ,","place":["China"]},{"name":"Biomedical Engineering Department, Institute of Advanced Clinical Medicine, Peking University , 5 Yiheyuan Rd, Haidian District, Beijing 100191 ,","place":["China"]},{"name":"Department of Dermatology and Venerology, Peking University First Hospital , 8 Xishiku Ave, Xicheng Distric, Beijing 100191 ,","place":["China"]},{"name":"State Key Laboratory of Molecular Oncology, Peking University International Cancer Institute , 5 Yiheyuan Rd, Haidian District, Beijing 100191 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