{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T21:48:26Z","timestamp":1785793706870,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,31]]},"group-title":"Nephrology","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"NIDDK","doi-asserted-by":"crossref","award":["R01-DK144793, R03DK144285, K25-DK128563"],"award-info":[{"award-number":["R01-DK144793, R03DK144285, K25-DK128563"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000051","name":"NHGRI","doi-asserted-by":"crossref","award":["5U01-HG008680"],"award-info":[{"award-number":["5U01-HG008680"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NLM","award":["R01LM013061"],"award-info":[{"award-number":["R01LM013061"]}]},{"DOI":"10.13039\/100006108","name":"NCATS","doi-asserted-by":"crossref","award":["UL1TR001873"],"award-info":[{"award-number":["UL1TR001873"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  While ultra-rare missense variants in\n                  <jats:italic>UMOD<\/jats:italic>\n                  cause highly penetrant autosomal dominant tubulointerstitial kidney disease, a more frequent\n                  <jats:italic>UMOD<\/jats:italic>\n                  T62P variant conveys intermediate risk with variable penetrance. To determine whether age or polygenic risk contributes to the variable penetrance of T62P, we combined genotype and phenotype data from 882,306 individuals across the UK Biobank (discovery cohort) and the All of Us and MyCode biobanks (validation cohorts). We also analyzed the impact of aging on uromodulin processing and cellular stress in stably transfected kidney tubular cells expressing wild-type or mutant\n                  <jats:italic>UMOD<\/jats:italic>\n                  . We compared the effects of the GPS on risk of CKD between T62P carriers and non-carriers and tested for the GPS-by-T62P interaction. The\n                  <jats:italic>UMOD<\/jats:italic>\n                  T62P variant was reproducibly associated with increased risk of CKD in an age-dependent manner. Compared to wild-type, clones of T62P-expressing cells exhibited a defective uromodulin maturation profile, causing endoplasmic reticulum retention and stress. We also observed significant T62P-by-GPS interaction, with T62P carriers in the top quintile of the GPS having over 5-fold higher risk of CKD compared to population average (OR 5.17, 95%CI: 2.94-9.08, P=1.0E-08). In summary, we demonstrate that the penetrance of kidney disease in T62P carriers is strongly modified by both age and polygenic risk.\n                <\/jats:p>","DOI":"10.64898\/2026.07.29.26359269","type":"posted-content","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T19:55:23Z","timestamp":1785527723000},"source":"Crossref","is-referenced-by-count":0,"title":["Uromodulin T62P variant causes kidney tubular stress and injury modulated by age and polygenic risk"],"prefix":"10.64898","author":[{"given":"Atlas","family":"Khan","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Gresch","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University of Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Olinger","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University of Zurich, Zurich, Switzerland"},{"name":"Center for Human Genetics, Cliniques universitaires Saint-Luc, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Mariniello","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University of Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Shang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Vanessa","family":"Perez Gomez","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, Health Research Institute-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), RICORS2040, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Dinsmore","sequence":"additional","affiliation":[{"name":"Department of Genomic Health, Geisinger, Danville, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly","family":"Mabillard","sequence":"additional","affiliation":[{"name":"Newcastle University, Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tooraj","family":"Mirshahi","sequence":"additional","affiliation":[{"name":"Department of Genomic Health, Geisinger, Danville, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander R","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Population of Health Sciences, Geisinger, Danville, PA, USA"},{"name":"Center for Kidney Health Research, Geisinger, Danville, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Devuyst","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University of Zurich, Zurich, Switzerland"},{"name":"Institute for Rare Diseases, Cliniques universitaires Saint-Luc, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof","family":"Kiryluk","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080314350993000_2026.07.29.26359269v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)30788-2"},{"key":"2026080314350993000_2026.07.29.26359269v1.2","doi-asserted-by":"crossref","unstructured":"Shang, N. , et al. 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