{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:18:29Z","timestamp":1792790309822,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,11]]},"group-title":"Genetic and Genomic Medicine","reference-count":25,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"publisher"}]},{"name":"The University of Texas Southwestern Medical Center","award":["04-2026"],"award-info":[{"award-number":["04-2026"]}],"id":[{"id":"https:\/\/ror.org\/05byvp690","id-type":"ROR","asserted-by":"crossref"}]},{"award":["ANR-10-IAHU-01"],"award-info":[{"award-number":["ANR-10-IAHU-01"]}],"id":[{"id":"https:\/\/ror.org\/00rbzpz17","id-type":"ROR","asserted-by":"publisher"}]},{"award":["ANR-10-LABX-62-IBEID"],"award-info":[{"award-number":["ANR-10-LABX-62-IBEID"]}],"id":[{"id":"https:\/\/ror.org\/00rbzpz17","id-type":"ROR","asserted-by":"publisher"}]},{"award":["EQU202503020018"],"award-info":[{"award-number":["EQU202503020018"]}],"id":[{"id":"https:\/\/ror.org\/04w6kn183","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Grandir \u2013 Fonds de solidarit\u00e9 pour l\u2019enfance"},{"name":"Fondation du Souffle","id":[{"id":"https:\/\/ror.org\/04qdyps56","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Square Foundation"},{"name":"SCOR Corporate Foundation for Science","id":[{"id":"https:\/\/ror.org\/04yh85858","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Battersea & Bowery Advisory Group"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  The 5\u2032 untranslated region (5\u2032UTR) regulates protein output through upstream open reading frames (uORFs) and Kozak context, yet most deleteriousness scores rely heavily on evolutionary conservation of its nucleotide positions. Using 5ULTRA, a machine-learning classifier trained on 5\u2032UTR regulatory biology, we annotated rare and low-frequency 5\u2032UTR variants in 408,423 UK Biobank participants. We tested gene-level associations for all 59 quantitative blood-count and serum biochemistry traits. We identified 58 genome-wide significant gene-phenotype associations and CADD 38, including 24 shared, 34 exclusive to 5ULTRA, and 14 to CADD. Removing 5ULTRA-annotated variants eliminated 15 of 38 CADD associations, indicating that a fraction of CADD\u2019s performance depends on uORF and Kozak architecture. The 18 associations absent from a published UK Biobank 5\u2032UTR study included 11 that were exclusive to 5ULTRA. Among these,\n                  <jats:italic>NELFCD<\/jats:italic>\n                  , a subunit of the RNA polymerase II pausing complex with no established role in megakaryopoiesis, reached \u2212log\u2081\u2080\n                  <jats:italic>P<\/jats:italic>\n                  = 50 for platelet distribution width. Associations were most often driven by variants predicted to suppress translation (13 of 16 directionally resolved associations;\n                  <jats:italic>P<\/jats:italic>\n                  = 0.021). Gene-level effects of 5\u2032UTR repressor variants correlated with those of coding protein-truncating variants (r = 0.68,\n                  <jats:italic>P<\/jats:italic>\n                  = 3.7 \u00d7 10\u207b\u2074), placing them on the same phenotypic scale. Associations tested in non-European participants showed 89% directional concordance (r = 0.84), supporting shared regulatory effects across ancestries. Mechanistic 5\u2032UTR annotation therefore recovers a translational layer of phenotypic variation that generic deleteriousness scores based on evolutionary constraints miss.\n                <\/jats:p>","DOI":"10.64898\/2026.09.09.26362607","type":"posted-content","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:45:12Z","timestamp":1789191912000},"source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic 5\u2019UTR Variant Scoring Expands Rare Variant Discovery in the UK Biobank"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4920-3947","authenticated-orcid":false,"given":"Matthieu","family":"Chaldebas","sequence":"first","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Universit\u00e9 Paris Cit\u00e9, Institut Imagine, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khoren","family":"Ponsin","sequence":"additional","affiliation":[{"name":"St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haralambos A.","family":"Mourelatos","sequence":"additional","affiliation":[{"name":"St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 10065, USA"},{"name":"Weill Cornell\/Rockefeller\/Memorial Sloan Kettering Tri-Institutional MD PhD Program, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoann","family":"Seeleuthner","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Institut Imagine, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e9ment","family":"Conil","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Institut Imagine, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Bohlen","sequence":"additional","affiliation":[{"name":"Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universit\u00e4t, Munich, Germany"},{"name":"Department of Pediatrics, Dr. von Hauner Childrens Hospital, LMU Klinikum, Munich, Germany"},{"name":"German Center for Child and Adolescent Health (DZKJ), Munich Site, Munich, Germany"},{"name":"Cluster for Nucleic Acid Sciences and Technologies \u2013 NUCLEATE, Feodor-Lynen-Str. 25, D-81377 M\u00fcnchen"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Laurent","family":"Casanova","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Universit\u00e9 Paris Cit\u00e9, Institut Imagine, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France"},{"name":"Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Universit\u00e9 Paris Cit\u00e9, Institut Imagine, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France"},{"name":"Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7209-6257","authenticated-orcid":false,"given":"Aur\u00e9lie","family":"Cobat","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Institut Imagine, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, 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