Critical genes in genitourinary embryogenesis are related to the development of adult hydrocele

Despite being a common urologic disorder with potentially complicated sequela, the genetic background of adult hydrocele has not previously been described. We performed a multi-population genome-wide association study of 363,460 men in the United Kingdom BioBank and FinnGen cohorts. We identified 6,548 adult men with hydrocele. We analyzed common variants (minor allele frequency > 0.01) associated with hydrocele and set the threshold for genome-wide significance at p < 5 × 10^− 8. Meta-analysis of genome-wide association studies identified 7 genome-wide significant loci which mapped to 24 genes. Multiple gene prioritization strategies highlighted PAX8, INHBB, AMHR2, and SHH, all known to be critical to genitourinary embryogenesis and associated with Mendelian genitourinary syndromes and model organism phenotypes. Identified loci affect gene expression in genitourinary structures and are associated with multiple markers of renal function. These common variants in genes critical for genitourinary embryogenesis are associated with adult hydrocele, suggesting these genes may maintain normal scrotal anatomy in adults. This large study of nearly 400,000 men is the first genomic study of idiopathic hydrocele and defines our current understanding of the genetic background of this common condition.