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It frequently overlaps with other autoimmune diseases (AIDs), including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, the genetic basis of SjD remains underexplored, limiting our understanding of its connections to other immune-mediated conditions. In this study, we aimed to identify gene networks associated with SjD through the integration of genetic, transcriptomic, and epigenomic data. We further compared the genetic factors of SjD with other immune-mediated diseases. We analyzed genome-wide association studies (GWAS) summary statistics, DNA methylation, and transcriptomic data using our in-house network-based methods, dmGWAS and EW_dmGWAS, to identify key gene modules associated with SjD. In dmGWAS analysis, discovery and evaluation datasets were used to identify consensus results. We conducted gene-set, cell-type, and disease-enrichment analyses on significant gene modules and explored potential drug targets. Genetic correlations and Mendelian randomization were applied to assess SjD\u2019s link with 17 other AIDs and 16 cancer types. dmGWAS identified 207 and 211 gene modules in the discovery and evaluation phases, respectively, while EW_dmGWAS detected 886 modules. Key modules highlighted 55 genes (discovery), 52 genes (evaluation), and 59 genes (EW_dmGWAS), with at least 50 genes from each analysis linked to AIDs and cancer. Enrichment analyses confirmed their relevance to immune and oncogenic pathways. We pinpointed four candidate drug targets associated with AIDs. We developed a novel integrative omics approach to identify potential genetic markers of SjD and compared them with AIDs and cancers. Our approach can be similarly applied to other disease studies.<\/jats:p>","DOI":"10.3390\/ijms26104637","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T03:59:26Z","timestamp":1747108766000},"page":"4637","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Genetic, Transcriptomic, and Epigenomic Insights into Sj\u00f6gren\u2019s Disease: An Integrative Network Investigation and Immune Diseases Comparison"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0255-706X","authenticated-orcid":false,"given":"Nitesh","family":"Enduru","sequence":"first","affiliation":[{"name":"Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA"},{"name":"Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid M.","family":"Manuel","sequence":"additional","affiliation":[{"name":"Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA"},{"name":"Molecular & Human Genetics Department, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3477-0914","authenticated-orcid":false,"given":"Zhongming","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA"},{"name":"Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1001\/archinte.164.12.1275","article-title":"Clinical manifestations and early diagnosis of Sjogren syndrome","volume":"164","author":"Kassan","year":"2004","journal-title":"Arch. 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