Congenital lower urinary tract obstructions (LUTO) are most often caused by posterior urethral valves (PUV), a male limited anatomical obstruction of the urethra affecting 1 in 4,000 male live births. Little is known about the genetic background of PUV. Here, we report the largest genome-wide association study (GWAS) for PUV in 4 cohorts of patients and controls. The final meta-analysis included 756 patients and 4,823 ethnicity matched controls and comprised 5,754,208 variants that were genotyped or imputed and passed quality control in all 4 cohorts. No genome-wide significant locus was identified, but 33 variants showed suggestive significance (P < 1 × 10-5). When considering only loci with multiple variants residing within < 10 kB of each other showing suggestive significance and with the same effect direction in all 4 cohorts, 3 loci comprising a total of 9 variants remained. These loci resided on chromosomes 13, 16, and 20. The present GWAS and meta-analysis is the largest genetic study on PUV performed to date. The fact that no genome-wide significant locus was identified, can be explained by lack of power or may indicate that common variants do not play a major role in the etiology of PUV. Nevertheless, future studies are warranted to replicate and validate the 3 loci that yielded suggestive associations.
Keywords: BMP7; PCDH9; SALL1; genome wide association study; lower urinary tract obstruction; obstructive uropathy; posterior urethral valves.
Copyright © 2022 van der Zanden, Maj, Borisov, van Rooij, Quaedackers, Steffens, Schierbaum, Schneider, Waffenschmidt, Kiemeney, de Wall, Heilmann, Hofmann, Gehlen, Schumacher, Szczepanska, Taranta-Janusz, Kroll, Krzemien, Szmigielska, Schreuder, Weber, Zaniew, Roeleveld, Reutter, Feitz and Hilger.