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 x 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.
Nature Genetics, 2014, Vol 46, Issue 9, p. 957-967
Denmark Europe Palearctic region; Netherlands Europe Palearctic region; Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae  human common female, male; human EYA1 gene [Hominidae] expression; human HOXA4 gene [Hominidae] expression; human IRX5 gene [Hominidae] expression; human IRX6 gene [Hominidae] expression; 03502, Genetics - General; 03508, Genetics - Human; 15504, Urinary system - Physiology and biochemistry; 15506, Urinary system - Pathology; 16504, Reproductive system - Physiology and biochemistry; 16506, Reproductive system - Pathology; 25503, Development and Embryology - Pathology; Molecular Genetics; Reproductive System; Urinary System; hypospadias Hypospadias (MeSH) urologic disease, reproductive system disease/female, reproductive system disease/male, congenital disease; DEPICT; GRAIL; Biochemistry and Molecular Biophysics; Chemical Coordination and Homeostasis; Reproduction; penis reproductive system; urethra reproductive system, excretory system; genome-wide association analyses laboratory techniques, genetic techniques; surgery therapeutic and prophylactic techniques, clinical techniques; GENETICS; DISEASE; LOCI; METAANALYSIS; EXPRESSION; MUTATIONS; RISK; DIFFERENTIATION; SUSCEPTIBILITY; IDENTIFICATION; POPULATION; HYPOSPADIAS; Genetic aspects