{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:14:11Z","timestamp":1785428051718,"version":"3.56.0"},"posted":{"date-parts":[[2025,6,8]]},"group-title":"Bioinformatics","reference-count":39,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,8]],"date-time":"2025-06-08T00:00:00Z","timestamp":1749340800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R00HG011898"],"award-info":[{"award-number":["R00HG011898"]}],"id":[{"id":"https:\/\/ror.org\/00baak391","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["R01HD109765"],"award-info":[{"award-number":["R01HD109765"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Down syndrome (DS) is caused by trisomy of chromosome 21 and is associated with diverse clinical manifestations, yet the molecular pathways linking chromosome-21 dosage effects to DS comorbidities remain poorly defined. Here we address this gap by applying a network-based, integrative framework that combines whole-blood transcriptomic data with gene-trait associations to uncover mechanistic insights into DS-associated conditions. First, we performed matrix factorization using PLIER on Human Trisome Project (HTP) RNA-Seq profiles from 304 trisomy-21 (T21) and 95 euploid (D21) individuals, deriving 156 biologically interpretable gene modules. We then identified 92 modules whose activity differed significantly between T21 and D21 and annotated these with prior-knowledge and KEGG pathways. To connect modules to clinical traits, we integrated PrediXcan-derived TWAS results from the UK Biobank, revealing 25 T21-specific modules with significant gene-trait associations (FDR &lt; 0.1), including modules linked to cardiovascular, hematological, immune, metabolic, and neurological phenotypes relevant to DS. Using HTP clinical records as a replication cohort, 13 of these modules reliably predicted comorbidity status (AUC &gt; 0.65, mAPS &gt; 0.65). Most notably module 37, an interferon-stimulated gene network, whose elevated expression robustly distinguished DS individuals with pulmonary hypertension (AUC = 0.76, mAPS = 0.73). Overall, our study demonstrates that integrating blood-derived gene modules with population-scale genetic data uncovers coherent molecular signatures underlying DS comorbidities, identifies candidate biomarkers and therapeutic targets (e.g.,\n                  <jats:italic>ISG15, IFITs, MX1<\/jats:italic>\n                  ), and highlights the power of combining transcriptomic and genetic evidence to elucidate complex disease mechanisms.\n                <\/jats:p>","DOI":"10.1101\/2025.06.05.658129","type":"posted-content","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T03:00:33Z","timestamp":1749438033000},"source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic insights into Down syndrome comorbidities via convergent RNA-seq and TWAS signals"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3934-839X","authenticated-orcid":false,"given":"Marc","family":"Subirana-Gran\u00e9s","sequence":"first","affiliation":[{"name":"Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6025-0217","authenticated-orcid":false,"given":"Haoyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3660-4415","authenticated-orcid":false,"given":"Prashant","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3035-4403","authenticated-orcid":false,"given":"Milton","family":"Pividori","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO 80045, USA"},{"name":"Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 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