{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:45:43Z","timestamp":1785422743013,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,2]]},"group-title":"Genomics","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01DK116954"],"award-info":[{"award-number":["R01DK116954"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,2]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  How cell type, sex and disease interact and affect gene expression and splicing is an important, but complicated question. Visualizing and testing specific hypotheses around these complex interactions is an important first step to identifying molecular components underpinning complex disease. Using a meta-analytical framework, we develop an analytical path for identifying testable molecular hypotheses of complex interactions between splicing, sex, disease and cell type. We focus on type 1 diabetes (T1D) but the approach is generalizable to any complex disease with defined candidate loci. Previous studies report T1D-associated splicing in candidate genes, differences in disease effects across immune cell types, sex effects on splicing and cell-type-specific splicing. However, identifying and interpreting complex interactions between sex, splicing and disease are challenging. Here we demonstrate how a gene expression study of T1D, designed to evaluate these interactions can be analyzed in a straightforward manner. We find that sex-dependent T1D-associated splicing is markedly more prevalent in CD4\u207a T cells than in CD8\u207a T cells, affecting 72% of T1D candidate genes in CD4\u207a cells compared to 30% in CD8\u207a cells. We pinpoint exons whose rate of inclusion is affected by the interaction of sex and disease. We use long-read RNAseq to identify novel intron retention events and splice sites which are quantified with short-reads leading to a richer description of the regulatory impact of T1D on alternative splicing. We identify a set of candidate isoforms for follow-up molecular studies in\n                  <jats:italic>BACH2<\/jats:italic>\n                  , a transcription factor known to be relevant in disease prevalence.\n                <\/jats:p>","DOI":"10.64898\/2026.05.29.728908","type":"posted-content","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T05:20:13Z","timestamp":1780464013000},"source":"Crossref","is-referenced-by-count":0,"title":["Sex and Alternative Splicing in Disease: a meta-analytic approach to identify interactions"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3921-7778","authenticated-orcid":false,"given":"Netanya","family":"Keil","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA,32610"},{"name":"University of Florida Genetics Institute, University of Florida, Gainesville, FL, USA, 32610"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Morse","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA,32610"},{"name":"University of Florida Genetics Institute, University of Florida, Gainesville, FL, USA, 32610"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Callahan","sequence":"additional","affiliation":[{"name":"University of Florida Genetics Institute, University of Florida, Gainesville, FL, USA, 32610"},{"name":"Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5801-1859","authenticated-orcid":false,"given":"Patrick","family":"Concannon","sequence":"additional","affiliation":[{"name":"University of Florida Genetics Institute, University of Florida, Gainesville, FL, USA, 32610"},{"name":"Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA"},{"name":"Diabetes Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0077-3359","authenticated-orcid":false,"given":"Lauren M","family":"McIntyre","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA,32610"},{"name":"University of Florida Genetics Institute, University of Florida, Gainesville, FL, USA, 32610"},{"name":"UF Health Cancer Center, University of Florida, Gainesville, FL, USA, 32610"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026060605400531000_2026.05.29.728908v1.1","doi-asserted-by":"crossref","unstructured":"Zhang, Y.J. , Qian, J.J. , Gu, C.Y. , and Yang, Y . (2021). Alternative splicing and cancer: a systematic review. Signal Transduction and Targeted Therapy 6.","DOI":"10.1038\/s41392-021-00486-7"},{"key":"2026060605400531000_2026.05.29.728908v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-023-00717-6"},{"key":"2026060605400531000_2026.05.29.728908v1.3","doi-asserted-by":"crossref","first-page":"713540","DOI":"10.3389\/fimmu.2021.713540","article-title":"Alternative splicing: a new cause and potential therapeutic target in autoimmune disease","volume":"12","year":"2021","journal-title":"Frontiers in Immunology"},{"key":"2026060605400531000_2026.05.29.728908v1.4","doi-asserted-by":"crossref","first-page":"462","DOI":"10.4161\/rna.7.4.12301","article-title":"Alternative splicing in multiple sclerosis and other autoimmune diseases","volume":"7","year":"2010","journal-title":"RNA biology"},{"key":"2026060605400531000_2026.05.29.728908v1.5","doi-asserted-by":"publisher","DOI":"10.1101\/gr.217984.116"},{"key":"2026060605400531000_2026.05.29.728908v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/nature07509"},{"key":"2026060605400531000_2026.05.29.728908v1.7","unstructured":"Consortium*, T.T.S. , Jones, R.C. , Karkanias, J. , Krasnow, M.A. , Pisco, A.O. , Quake, S.R. , Salzman, J. , Yosef, N. , Bulthaup, B. , and Brown, P. (2022). The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans. Science 376, eabl4896."},{"key":"2026060605400531000_2026.05.29.728908v1.8","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.molimm.2021.02.009","article-title":"A comparison of alternative mRNA splicing in the CD4 and CD8 T cell lineages","volume":"133","year":"2021","journal-title":"Molecular Immunology"},{"key":"2026060605400531000_2026.05.29.728908v1.9","unstructured":"Karlebach, G. , Veiga, D.F.T. , Mays, A.D. , Chatzipantsiou, C. , Barja, P.P. , Chatzou, M. , Kesarwani, A.K. , Danis, D. , Kararigas, G. , Zhang, X.A. , et al. (2020). The impact of biological sex on alternative splicing. bioRxiv, 490904."},{"key":"2026060605400531000_2026.05.29.728908v1.10","doi-asserted-by":"crossref","first-page":"2771","DOI":"10.1038\/ncomms3771","article-title":"Widespread sex differences in gene expression and splicing in the adult human brain","volume":"4","year":"2013","journal-title":"Nature communications"},{"key":"2026060605400531000_2026.05.29.728908v1.11","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-255000"},{"key":"2026060605400531000_2026.05.29.728908v1.12","first-page":"1","article-title":"Sex differences in autoimmune diseases","volume":"2","year":"2011","journal-title":"Biology of Sex Differences"},{"key":"2026060605400531000_2026.05.29.728908v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/S1568-9972(03)00006-5"},{"key":"2026060605400531000_2026.05.29.728908v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecl.2010.05.011"},{"key":"2026060605400531000_2026.05.29.728908v1.15","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2007.01896.x"},{"key":"2026060605400531000_2026.05.29.728908v1.16","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1016\/S0140-6736(08)60765-5","article-title":"Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study","volume":"371","year":"2008","journal-title":"The Lancet"},{"key":"2026060605400531000_2026.05.29.728908v1.17","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1042\/CS20160998","article-title":"Sex differences in micro- and macro-vascular complications of diabetes mellitus","volume":"131","year":"2017","journal-title":"Clin Sci (Lond"},{"key":"2026060605400531000_2026.05.29.728908v1.18","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1007\/s00125-022-05866-4","article-title":"Do sex differences in paediatric type 1 diabetes care exist? A systematic review","volume":"66","year":"2023","journal-title":"Diabetologia"},{"key":"2026060605400531000_2026.05.29.728908v1.19","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/S2213-8587(14)70248-7","article-title":"Risk of all-cause mortality and vascular events in women versus men with type 1 diabetes: a systematic review and meta-analysis","volume":"3","year":"2015","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2026060605400531000_2026.05.29.728908v1.20","doi-asserted-by":"crossref","first-page":"6857","DOI":"10.1111\/dom.70124","article-title":"Sex as a modifier of genetic risk for type 1 diabetes. Diabetes","volume":"27","year":"2025","journal-title":"Obesity and Metabolism"},{"key":"2026060605400531000_2026.05.29.728908v1.21","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s13293-024-00595-2","article-title":"Consideration of sex as a biological variable in diabetes research across twenty years","volume":"15","year":"2024","journal-title":"Biology of Sex Differences"},{"key":"2026060605400531000_2026.05.29.728908v1.22","doi-asserted-by":"crossref","unstructured":"Christianson, S.W. , Shultz, L.D. , and Leiter, E.H . (1993). Adoptive transfer of diabetes into immunodeficient NOD-scid\/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. Diabetes 42, 44-55.","DOI":"10.2337\/diabetes.42.1.44"},{"key":"2026060605400531000_2026.05.29.728908v1.23","doi-asserted-by":"publisher","DOI":"10.1900\/RDS.2009.6.97"},{"key":"2026060605400531000_2026.05.29.728908v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2776(08)00804-3"},{"key":"2026060605400531000_2026.05.29.728908v1.25","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3389\/fendo.2017.00343","article-title":"T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes","volume":"8","year":"2017","journal-title":"Front Endocrinol (Lausanne"},{"key":"2026060605400531000_2026.05.29.728908v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00880-5"},{"key":"2026060605400531000_2026.05.29.728908v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3245"},{"key":"2026060605400531000_2026.05.29.728908v1.28","doi-asserted-by":"publisher","DOI":"10.2337\/db16-1023"},{"key":"2026060605400531000_2026.05.29.728908v1.29","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.4049\/jimmunol.1801338","article-title":"UBASH3A regulates the synthesis and dynamics of TCR\u2013CD3 complexes","volume":"203","year":"2019","journal-title":"The Journal of Immunology"},{"key":"2026060605400531000_2026.05.29.728908v1.30","doi-asserted-by":"publisher","DOI":"10.2337\/db21-0194"},{"key":"2026060605400531000_2026.05.29.728908v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/ng1323"},{"key":"2026060605400531000_2026.05.29.728908v1.32","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/sj.gene.6364138","article-title":"A functional polymorphism (1858C\/T) in the PTPN22 gene is linked and associated with type I diabetes in multiplex families","volume":"5","year":"2004","journal-title":"Genes & Immunity"},{"key":"2026060605400531000_2026.05.29.728908v1.33","doi-asserted-by":"publisher","DOI":"10.2337\/db15-0322"},{"key":"2026060605400531000_2026.05.29.728908v1.34","doi-asserted-by":"crossref","unstructured":"Atla, G. , Bon\u00e0s-Guarch, S. , Cuenca-Ardura, M. , Beucher, A. , Crouch, D.J.M. , Garcia-Hurtado, J. , Moran, I. , Consortium, T.D. , Irimia, M. , Prasad, R.B. , et al. (2022). Genetic regulation of RNA splicing in human pancreatic islets. In Genome biology. p 196.","DOI":"10.1101\/2021.11.11.468254"},{"key":"2026060605400531000_2026.05.29.728908v1.35","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/dom.13388","article-title":"When one becomes many\u2014Alternative splicing in \u03b2-cell function and failure. Diabetes","volume":"20","year":"2018","journal-title":"Obesity and Metabolism"},{"key":"2026060605400531000_2026.05.29.728908v1.36","doi-asserted-by":"crossref","unstructured":"Newman, J.R.B. , Concannon, P. , Tardaguila, M. , Conesa, A. , and McIntyre, L.M . (2018). Event Analysis: Using Transcript Events To Improve Estimates of Abundance in RNA-seq Data. G3 Genes|Genomes|Genetics 8, 2923-2940.","DOI":"10.1534\/g3.118.200373"},{"key":"2026060605400531000_2026.05.29.728908v1.37","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1038\/s41592-024-02298-3","article-title":"Systematic assessment of long-read RNA-seq methods for transcript identification and quantification","volume":"21","year":"2024","journal-title":"Nature Methods"},{"key":"2026060605400531000_2026.05.29.728908v1.38","doi-asserted-by":"publisher","DOI":"10.1177\/1740774510373497"},{"key":"2026060605400531000_2026.05.29.728908v1.39","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1210\/clinem\/dgaf181","article-title":"Type 1 Diabetes Genetics Consortium","volume":"110","year":"2025","journal-title":"J Clin Endocrinol Metab"},{"key":"2026060605400531000_2026.05.29.728908v1.40","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/s41592-024-02229-2","article-title":"SQANTI3: curation of long-read transcriptomes for accurate identification of known and novel isoforms","volume":"21","year":"2024","journal-title":"Nature Methods"},{"key":"2026060605400531000_2026.05.29.728908v1.41","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae056"},{"key":"2026060605400531000_2026.05.29.728908v1.42","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-11-94"},{"key":"2026060605400531000_2026.05.29.728908v1.43","first-page":"1","article-title":"Conducting meta-analyses in R with the metafor package","volume":"36","year":"2010","journal-title":"Journal of statistical software"},{"key":"2026060605400531000_2026.05.29.728908v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2705"},{"key":"2026060605400531000_2026.05.29.728908v1.45","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/s42003-023-05327-7","article-title":"Shifts in isoform usage underlie transcriptional differences in regulatory T cells in type 1 diabetes","volume":"6","year":"2023","journal-title":"Communications Biology"},{"key":"2026060605400531000_2026.05.29.728908v1.46","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-05-078154"},{"key":"2026060605400531000_2026.05.29.728908v1.47","doi-asserted-by":"publisher","DOI":"10.3109\/02713683.2014.958500"},{"key":"2026060605400531000_2026.05.29.728908v1.48","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-019-4926-x"},{"key":"2026060605400531000_2026.05.29.728908v1.49","doi-asserted-by":"crossref","unstructured":"Madonna, R. , Balistreri, C.R. , De Rosa, S. , Muscoli, S. , Selvaggio, S. , Selvaggio, G. , Ferdinandy, P. , and De Caterina, R. (2019). Impact of Sex Differences and Diabetes on Coronary Atherosclerosis and Ischemic Heart Disease. J Clin Med 8.","DOI":"10.3390\/jcm8010098"},{"key":"2026060605400531000_2026.05.29.728908v1.50","doi-asserted-by":"crossref","first-page":"e70270","DOI":"10.1096\/fj.202402354R","article-title":"Sex-specific cytokine, chemokine, and growth factor signatures in T1D patients and progressors","volume":"38","year":"2024","journal-title":"Faseb j"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.29.728908","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T12:40:18Z","timestamp":1780749618000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.05.29.728908"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,2]]},"references-count":50,"URL":"https:\/\/doi.org\/10.64898\/2026.05.29.728908","relation":{},"subject":[],"published":{"date-parts":[[2026,6,2]]},"subtype":"preprint"}}