Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6 × 10⁻¹¹). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk. ; This research was supported by the following grants: British Heart Foundation (BHF) Chair CH/98001 to AFD; BHF Programme RG/07/005/23633 to AFD, SP, CD; BHF Special Project Grant SP/08/005/25115 to AFD, SP, CD; SP was supported by an intermediate research fellowship from the BHF (FS/05/095/19937). We thank the British Heart Foundation, European Community Framework 6 Network of Excellence InGenious HyperCare, Fondazione Istituto Auxologico Italiano, and Regione Lombardia for funding the discovery study and validation in the MONICA/PAMELA populations. The discovery study and validations in the MONICA/PAMELA populations are part of the activities of the EC Network of Excellence InGenious HyperCare (LSMH-CT-2006-037093) coordinated by Prof. A Zanchetti. Further financial support has been provided by Fondazione Istituto Auxologico Italiano, Milan, and Regione Lombardia. ; 20790