Uromodulin T62P variant causes kidney tubular stress and injury modulated by age and polygenic risk.

While ultra-rare missense variants in UMOD cause highly penetrant autosomal dominant tubulointerstitial kidney disease, a more frequent UMOD 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 UMOD. 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 UMOD 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.