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

Frank Geller, Bjarke Feenstra, Lisbeth Carstensen, Tune H. Pers, Iris A. L. M. van Rooij, Izabella Baranowska Korberg, Shweta Choudhry, Juha M. Karjalainen, Tine H. Schnack, Mads V. Hollegaard, Wout F. J. Feitz, Nel Roeleveld, David M. Hougaard, Joel N. Hirschhorn, Lude Franke, Laurence S. Baskin, Agneta Nordenskjold, Loes F. M. van der Zanden, Mads Melbye

    Research output: Contribution to journalJournal articleResearchpeer-review


    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.
    Original languageEnglish
    JournalNature Genetics
    Issue number9
    Pages (from-to)957-967
    Number of pages10
    Publication statusPublished - 2014


    • 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
    • LOCI
    • RISK
    • Genetic aspects


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