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However, this is hindered by limited scRNA\u2010seq sample size and the lack of cellular resolution in biobanks. We present CausalCellInfer, a scalable computational framework bringing cellular resolution to bulk and genotype\u2010imputed transcriptomes. CausalCellInfer employs an invariant causal prediction\u2010inspired method(scRNA\u2010seq\u2010based invariant generalized covariance measure, scI\u2010GCM) to select environment\u2010stable marker genes, a parsimonious deep neural network for cell\u2010fraction deconvolution, and regularized matrix completion to reconstruct cell\u2010type\u2010specific (CTS) expression profiles. This design is optimized for biobank\u2010scale data with technical heterogeneity and limited gene overlap. Validated across simulated data, pseudo\u2010bulk and real peripheral blood mononuclear cell (PBMC) datasets, CausalCellInfer demonstrated superior accuracy and efficiency over existing methods. Applied to \u223c500\u00a0000 UK Biobank (UKBB) participants across 29 traits, it captured known pathological shifts, such as reduced pancreatic \u03b2\u2010cell proportions in type 2 diabetes, and identified novel biological signals, including disrupted excitatory neuron\u2010oligodendrocyte interactions in depression. Inferred CTS differential expression patterns showed significant concordance with independent single\u2010cell studies and were enriched for Open Targets disease genes. Overall, CausalCellInfer bridges single\u2010cell insights and population\u2010scale genomics, enabling systematic discovery of putative disease mechanisms at cellular resolution.<\/jats:p>","DOI":"10.1002\/advs.78197","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:16:28Z","timestamp":1792034188000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CausalCellInfer: Prioritizing Cell\u2010Type\u2010Specific Disease Associations From Genetically Predicted Transcriptomes in Biobank Cohorts"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1029-7317","authenticated-orcid":false,"given":"Liangying","family":"Yin","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences The Chinese University of Hong Kong Shatin Hong Kong SAR China"},{"name":"Eric and Wendy Schmidt Center Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujia","family":"Shi","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences The Chinese University of Hong Kong Shatin Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences The Chinese University of Hong Kong Shatin Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Xiang","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences The Chinese University of Hong Kong Shatin Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghong","family":"Qiu","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences The Chinese University of Hong Kong Shatin Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pak\u2010Chung","family":"Sham","sequence":"additional","affiliation":[{"name":"Department of Psychiatry The University of Hong Kong Hong Kong Island Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7102-833X","authenticated-orcid":false,"given":"Hon\u2010Cheong","family":"So","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences The Chinese University of Hong Kong Shatin Hong Kong SAR China"},{"name":"KIZ\u2010CUHK Joint Laboratory of Bioresources and Molecular Research of Common Diseases Kunming Institute of Zoology and The Chinese University of Hong Kong  Kunming China"},{"name":"Department of Psychiatry The Chinese University of Hong Kong Hong Kong SAR China"},{"name":"CUHK Shenzhen Research Institute  Shenzhen China"},{"name":"Margaret K.L. 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