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

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Abstract

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.

Denmark Europe Palearctic region Netherlands Europe Palearctic region Primates Mammalia Vertebrata Chordata Animalia (Animals Chordates Humans Mammals Primates Vertebrates) - Hominidae [86215] 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