Genome-wide association analyses identify variants in developmental genes associated with hypospadias

Frank Geller and colleagues report the results of a large genome-wide association study of hypospadias. They identify 18 susceptibility regions for this common congenital condition, many of which harbor genes important for embryonic development. Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1,812 controls from Denmark, the Netherlands and Sweden, 18 genomic regions showed independent association with P < 5 × 10 −8 . Together, these loci explain 9% of the liability to developing this condition. Several of the identified regions harbor genes with key roles in embryonic development (including HOXA4 , IRX5 , IRX6 and EYA1 ). Subsequent pathway analysis with GRAIL and DEPICT provided additional insight into possible genetic mechanisms causing hypospadias.