{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T19:12:49Z","timestamp":1776193969372,"version":"3.50.1"},"reference-count":0,"publisher":"Oxford University Press (OUP)","issue":"Supplement_1","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":11,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Genome-wide association studies (GWAS) have revealed numerous loci for complex diseases, yet the cellular contexts through which these variants act remain poorly understood. Single-cell RNA sequencing (scRNA-seq) offers high-resolution profiling of cellular heterogeneity, but linking GWAS signals to disease-relevant cells remains a challenge.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We developed a statistical framework that integrates GWAS-prioritized genes with single-cell transcriptomes to detect disease-relevant cells. Each target cell is contrasted with pools of healthy reference cells, ensuring that differences reflect disease rather than technical variability. Two controls are implemented: reference cells matched by sequencing depth and expression-matched control genes without known disease associations. Iterative Monte Carlo sampling generates comparisons across random draws of reference cells and control genes, reducing stochastic noise. A difference-of-differences statistic captures disease-specific shifts, with Fisher\u2019s method aggregating significance and enrichment tests identifying cell types overrepresented in patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In simulations and real-world datasets, the framework showed strong performance. In large peripheral blood cohorts, it consistently identified trait-associated populations, with monocytes as a benchmark. Analyses of disease datasets revealed both established and novel pathogenic populations, including age-associated B cells and cytotoxic CD8+ T cells in systemic lupus erythematosus, antigen-presenting acinar cells in Sj\u00f6gren\u2019s syndrome, and dysregulated proximal tubules in chronic kidney disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings demonstrate the utility of integrating GWAS with single-cell transcriptomics to pinpoint disease-relevant cells in complex traits.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bib\/bbaf631.071","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T14:14:31Z","timestamp":1765548871000},"page":"i40-i40","source":"Crossref","is-referenced-by-count":1,"title":["A framework for integrating GWAS and single-cell RNA-seq with healthy reference controls to identify disease-associated cells"],"prefix":"10.1093","volume":"26","author":[{"given":"Caicai","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, The University of Hong Kong ,","place":["Hong Kong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank Qingyun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, The University of Hong Kong ,","place":["Hong Kong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao","family":"Dang","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, The University of Hong Kong ,","place":["Hong Kong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huidong","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, The University of Hong Kong ,","place":["Hong Kong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingtian","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, The University of Hong Kong ,","place":["Hong Kong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, The University of Hong Kong ,","place":["Hong Kong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youming","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, The University of Hong Kong ,","place":["Hong Kong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinxin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, The University of Hong Kong ,","place":["Hong Kong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanling","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, The University of Hong Kong ,","place":["Hong Kong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,12,12]]},"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/26\/Supplement_1\/i40\/65854405\/bbaf631.071.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/26\/Supplement_1\/i40\/65854405\/bbaf631.071.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T15:49:26Z","timestamp":1766764166000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/26\/Supplement_1\/i40\/8377992"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":0,"journal-issue":{"issue":"Supplement_1","published-print":{"date-parts":[[2025,12,12]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbaf631.071","relation":{},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"value":"1467-5463","type":"print"},{"value":"1477-4054","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,12]]},"published":{"date-parts":[[2025,12]]}}}