{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T12:52:37Z","timestamp":1781527957924,"version":"3.54.1"},"posted":{"date-parts":[[2026,6,12]]},"group-title":"Genetic and Genomic Medicine","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01CA269589-01A1"],"award-info":[{"award-number":["R01CA269589-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01CA297582"],"award-info":[{"award-number":["R01CA297582"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01CA285851"],"award-info":[{"award-number":["R01CA285851"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Bulk tissue-based DNA methylation-wide (MWAS) and transcriptome-wide association studies (TWAS) have identified CpG sites and genes associated with colorectal cancer (CRC) risk, but do not account for cellular heterogeneity. To address this, we developed a deconvolution-informed framework to infer cell-type specific DNA methylation and gene expression profiles from bulk normal colon tissues using reference single-cell epigenomic and transcriptomic datasets. We performed cell-type specific MWAS (ctMWAS) using deconvoluted DNA methylation data from 293 normal colon samples and conducted cell-type specific TWAS (ctTWAS) using deconvoluted gene expression data from 707 normal colon samples. Genetically predicted methylation and expression models were integrated with CRC GWAS summary statistics (78,473 cases and 107,143 controls) to identify risk-associated CpG sites and genes. Through ctMWAS, ctTWAS, and colocalization analyses, we identified 178 high-confidence cell-type-specific CpG sites and 68 genes associated with CRC across 26 previously unreported GWAS loci. Through additional integrative methylation-gene analysis, we prioritized 132 candidate risk genes, the majority of which were supported by multi-omics evidence and stage-specific dysregulation across the adenoma-carcinoma and serrated-carcinoma progression pathways. Pathway enrichment analyses implicated pathways involved in DNA double-strand break repair, TP53 regulation, TGF-\u03b2 signaling, and innate immune responses. Among prioritized genes, 14 were identified as putative druggable targets linked to 90 FDA-approved or clinical-stage drugs. Experimental validation supports an oncogenic role for\n                  <jats:italic>SF3A3<\/jats:italic>\n                  . These findings demonstrate that deconvolution-informed integrative analyses enable cell-type-resolved identification of epigenetic and transcriptional mechanisms underlying CRC susceptibility and provide insights into disease biology, prevention, and therapeutic target discovery.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    We developed a deconvolution-informed, cell-type specific multi-omics framework that identified CRC risk-associated CpG sites and susceptibility genes, revealing cell-type specific regulatory mechanisms, key biological pathways, and druggable targets relevant to CRC prevention, therapeutic development, and drug repurposing. Functional validation further supports\n                    <jats:italic>SF3A3<\/jats:italic>\n                    as a potential oncogenic driver in colorectal carcinogenesis.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.11.26355460","type":"posted-content","created":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:45:19Z","timestamp":1781311519000},"source":"Crossref","is-referenced-by-count":0,"title":["Deconvolution-based cell-type specific DNA methylation-wide and transcriptome-wide association studies identify risk CpG sites and genes associated with colorectal cancer risk"],"prefix":"10.64898","author":[{"given":"Qing","family":"Li","sequence":"first","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Xu","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jifeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanqing","family":"Wen","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Shu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaohua","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, UVA Comprehensive Cancer Center, School of Medicine, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3815-7172","authenticated-orcid":false,"given":"Xiao-ou","family":"Shu","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyin","family":"Cai","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jirong","family":"Long","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhuminder","family":"Singh","sequence":"additional","affiliation":[{"name":"Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken S","family":"Lau","sequence":"additional","affiliation":[{"name":"Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijun","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Casey","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, UVA Comprehensive Cancer Center, School of Medicine, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyang","family":"Song","sequence":"additional","affiliation":[{"name":"Departments of Epidemiology and Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Peters","sequence":"additional","affiliation":[{"name":"Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"name":"Department of Epidemiology, School of Public Health, University of Washington Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zheng","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyi","family":"Guo","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA"},{"name":"Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061505001003000_2026.06.11.26355460v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01222-9"},{"key":"2026061505001003000_2026.06.11.26355460v1.2","doi-asserted-by":"crossref","first-page":"3557","DOI":"10.1038\/s41467-024-47399-x","article-title":"Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes","volume":"15","year":"2024","journal-title":"Nat Commun"},{"key":"2026061505001003000_2026.06.11.26355460v1.3","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1038\/s41588-024-01900-w","article-title":"Systematic prioritization of functional variants and effector genes underlying colorectal cancer risk","volume":"56","year":"2024","journal-title":"Nat Genet"},{"key":"2026061505001003000_2026.06.11.26355460v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.09.082"},{"key":"2026061505001003000_2026.06.11.26355460v1.5","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-1059"},{"key":"2026061505001003000_2026.06.11.26355460v1.6","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0296"},{"key":"2026061505001003000_2026.06.11.26355460v1.7","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1186\/s13148-021-01148-9","article-title":"Identifying causal models between genetically regulated methylation patterns and gene expression in healthy colon tissue","volume":"13","year":"2021","journal-title":"Clin Epigenetics"},{"key":"2026061505001003000_2026.06.11.26355460v1.8","doi-asserted-by":"crossref","first-page":"6071","DOI":"10.1038\/s41467-024-50404-y","article-title":"Integrating muti-omics data to identify tissue-specific DNA methylation biomarkers for cancer risk","volume":"15","year":"2024","journal-title":"Nat Commun"},{"key":"2026061505001003000_2026.06.11.26355460v1.9","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1093\/hmg\/ddab021","article-title":"Multi-omics analysis to identify susceptibility genes for colorectal cancer","volume":"30","year":"2021","journal-title":"Hum Mol Genet"},{"key":"2026061505001003000_2026.06.11.26355460v1.10","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.08.062"},{"key":"2026061505001003000_2026.06.11.26355460v1.11","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1093\/jnci\/djad178","article-title":"Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation","volume":"116","year":"2024","journal-title":"J Natl Cancer Inst"},{"key":"2026061505001003000_2026.06.11.26355460v1.12","doi-asserted-by":"crossref","unstructured":"Chen Z , Song W , Li Q , Li C , Wen W , Huyghe JR , et al. Mixed-model and transcriptome-wide association analyses identify transcription factors and genes associated with colorectal cancer susceptibility. Nat Commun 2026","DOI":"10.1038\/s41467-025-68127-z"},{"key":"2026061505001003000_2026.06.11.26355460v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-60275-6"},{"key":"2026061505001003000_2026.06.11.26355460v1.14","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1158\/2159-8290.CD-24-1561","article-title":"Single-cell eQTL Mapping Reveals Cell Subtype-specific Genetic Control and Mechanism in Malignant Transformation of Colorectal Cancer","volume":"15","year":"2025","journal-title":"Cancer Discov"},{"key":"2026061505001003000_2026.06.11.26355460v1.15","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.ajhg.2025.11.008","article-title":"Large-scale integration of omics and electronic health records to identify potential risk protein biomarkers and therapeutic drugs for cancer prevention","volume":"113","year":"2026","journal-title":"Am J Hum Genet"},{"key":"2026061505001003000_2026.06.11.26355460v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-022-01412-7"},{"key":"2026061505001003000_2026.06.11.26355460v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0114-2"},{"key":"2026061505001003000_2026.06.11.26355460v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34888-0"},{"key":"2026061505001003000_2026.06.11.26355460v1.19","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/s41597-022-01697-5","article-title":"COLONOMICS - integrative omics data of one hundred paired normal-tumoral samples from colon cancer patients","volume":"9","year":"2022","journal-title":"Sci Data"},{"key":"2026061505001003000_2026.06.11.26355460v1.20","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz1776"},{"key":"2026061505001003000_2026.06.11.26355460v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01248-z"},{"key":"2026061505001003000_2026.06.11.26355460v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.11.031"},{"key":"2026061505001003000_2026.06.11.26355460v1.23","first-page":"A68","article-title":"The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge","volume":"19","year":"2015","journal-title":"Contemp Oncol (Pozn"},{"key":"2026061505001003000_2026.06.11.26355460v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.06.009"},{"key":"2026061505001003000_2026.06.11.26355460v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-024-00763-x"},{"key":"2026061505001003000_2026.06.11.26355460v1.26","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad976"},{"key":"2026061505001003000_2026.06.11.26355460v1.27","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1004"},{"key":"2026061505001003000_2026.06.11.26355460v1.28","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad751"},{"key":"2026061505001003000_2026.06.11.26355460v1.29","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKAA1027"},{"key":"2026061505001003000_2026.06.11.26355460v1.30","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-02126-9"},{"key":"2026061505001003000_2026.06.11.26355460v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15816-6"},{"key":"2026061505001003000_2026.06.11.26355460v1.32","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2026061505001003000_2026.06.11.26355460v1.33","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts196"},{"key":"2026061505001003000_2026.06.11.26355460v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2011.457"},{"key":"2026061505001003000_2026.06.11.26355460v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03621-1"},{"key":"2026061505001003000_2026.06.11.26355460v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2019.01.002"},{"key":"2026061505001003000_2026.06.11.26355460v1.37","doi-asserted-by":"crossref","unstructured":"Zhang Y , Chen F , Chandrashekar DS , Varambally S , Creighton CJ. Proteogenomic characterization of 2002 human cancers reveals pan-cancer molecular subtypes and associated pathways. Nat Commun 2022;13:2669","DOI":"10.1038\/s41467-022-30342-3"},{"key":"2026061505001003000_2026.06.11.26355460v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.11.031"},{"key":"2026061505001003000_2026.06.11.26355460v1.39","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2026061505001003000_2026.06.11.26355460v1.40","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw377"},{"key":"2026061505001003000_2026.06.11.26355460v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30481-7"},{"key":"2026061505001003000_2026.06.11.26355460v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.01.034"},{"key":"2026061505001003000_2026.06.11.26355460v1.43","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/s41698-025-00906-9","article-title":"Trans-ancestry transcriptome-wide association and functional studies to uncover novel susceptibility genes and therapeutic targets for colorectal cancer","volume":"9","year":"2025","journal-title":"NPJ Precis Oncol"},{"key":"2026061505001003000_2026.06.11.26355460v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/srep07596"},{"key":"2026061505001003000_2026.06.11.26355460v1.45","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2020.11851"},{"key":"2026061505001003000_2026.06.11.26355460v1.46","doi-asserted-by":"crossref","first-page":"114667","DOI":"10.1016\/j.celrep.2024.114667","article-title":"The TRIM4 E3 ubiquitin ligase degrades TPL2 and is modulated by oncogenic KRAS","volume":"43","year":"2024","journal-title":"Cell Rep"},{"key":"2026061505001003000_2026.06.11.26355460v1.47","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s11684-024-1103-5","article-title":"TRIM4 modulates the ubiquitin-mediated degradation of hnRNPDL and weakens sensitivity to CDK4\/6 inhibitor in ovarian cancer","volume":"19","year":"2025","journal-title":"Front Med"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.11.26355460","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T12:00:21Z","timestamp":1781524821000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.06.11.26355460"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,12]]},"references-count":47,"URL":"https:\/\/doi.org\/10.64898\/2026.06.11.26355460","relation":{},"subject":[],"published":{"date-parts":[[2026,6,12]]},"subtype":"preprint"}}