<p>This study examines the genetic susceptibility and pathogenesis of hypospadias. Hypospadias is a birth defect of the urethra where the urinary opening is on the underside of the penis rather than at the tip. This study aims to identify the genetic basis of this defect and, by extension, improve our understanding of the biological pathways involved in its pathogenesis. Novel genetic loci and variants associated with hypospadias were identified through case–control studies in Europe and North America and, more recently, through large-scale genome-wide association studies (GWAS). The identified genetic loci may be crucial in gene regulation or expression associated with penile development, or they may increase susceptibility to environmental factors that increases the occurrence of hypospadias. Moreover, analysis of associated variants revealed that most variants have a modest effect on hypospadas risk. To better understand the underlying biological pathways, data-driven approaches such as gene expression and epigenetic analysis are being used to identify gene networks and regulatory regions relevant to hypospadias pathogenesis. In conclusion, this study provides a comprehensive overview of genetic susceptibility and pathogenesis of hypospadias and highlights the need for further research into the role of genetic and environmental factors in the onset and progression of this defect.</p> Graphical Abstract <p></p>