Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin
Authors: Joseph Christina B. , Mariniello Marta , Yoshifuji Ayumi , Schiano Guglielmo , Lake Jennifer , Marten Jonathan , Richmond Anne , Huffman Jennifer E. , Campbell Archie , Harris Sarah E. , Troyanov Stephan , Cocca Massimiliano , Robino Antonietta , Thériault Sébastien , Eckardt Kai-Uwe , Wuttke Matthias , Cheng Yurong , Corre Tanguy , Kolcic Ivana , Black Corrinda , Bruat Vanessa , Concas Maria Pina , Sala Cinzia , Aeschbacher Stefanie , Schaefer Franz , Bergmann Sven , Campbell Harry , Olden Matthias , Polasek Ozren , Porteous David J. , Deary Ian J. , Madore Francois , Awadalla Philip , Girotto Giorgia , Ulivi Sheila , Conen David , Wuehl Elke , Olinger Eric , Wilson James F. , Bochud Murielle , Köttgen Anna , Hayward Caroline , Devuyst Olivier 
Published: February 2022

Significance Statement
The mechanisms regulating the urinary excretion of uromodulin remain mostly unknown. A meta-GWAS conducted in 29,315 individuals from 13 cohorts identified two novel, genome-wide significant loci, KRT40 and WDR72, in addition to the previously known UMOD-PDILT locus, to be associated with urinary uromodulin. KRT40 colocalizes with uromodulin in TAL cells and functional studies showed that its expression affects the processing and apical excretion of uromodulin. WDR72, which does not colocalize with uromodulin, has been associated with kidney function, urinary acidification, and kidney stones. These studies provide novel insights into the biology of uromodulin and keratins and into the influence of the UMOD-PDILT locus on kidney function.

Background
Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown.

Methods
We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing.

Results
Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E–08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E–88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion.

Conclusions
Common variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.