title: Genome-wide association analyses identify variants in developmental genes associated with hypospadias.
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 × 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.
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Frank
authors.initials: F
authors.lastname: Geller
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Bjarke
authors.initials: B
authors.lastname: Feenstra
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Carstensen
authors.affiliation: 1] Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [4] Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Tune H
authors.initials: TH
authors.lastname: Pers
authors.affiliation: Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Iris A L M
authors.initials: IA
authors.lastname: van Rooij
authors.affiliation: 1] Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. [2] Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Izabella Baranowska
authors.initials: IB
authors.lastname: Körberg
authors.affiliation: Department of Urology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Shweta
authors.initials: S
authors.lastname: Choudhry
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Juha M
authors.initials: JM
authors.lastname: Karjalainen
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Tine H
authors.initials: TH
authors.lastname: Schnack
authors.affiliation: Danish Centre for Neonatal Screening, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Mads V
authors.initials: MV
authors.lastname: Hollegaard
authors.affiliation: Department of Urology, Pediatric Urology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Wout F J
authors.initials: WF
authors.lastname: Feitz
authors.affiliation: 1] Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands. [2] Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Nel
authors.initials: N
authors.lastname: Roeleveld
authors.affiliation: Danish Centre for Neonatal Screening, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: David M
authors.initials: DM
authors.lastname: Hougaard
authors.affiliation: 1] Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [4] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: Department of Urology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Laurence S
authors.initials: LS
authors.lastname: Baskin
authors.affiliation: 1] Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. [2] Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordenskjöld
authors.affiliation: Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Loes F M
authors.initials: LF
authors.lastname: van der Zanden
authors.affiliation: 1] Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. [2] Department of Medicine, Stanford School of Medicine, Stanford, California, USA.
authors.forename: Mads
authors.initials: M
authors.lastname: Melbye
mesh_terms: D016022:Case-Control Studies; D003718:Denmark; D005260:Female; D050437:Genes, Developmental; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D007021:Hypospadias / Q000235:genetics*; D008297:Male; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D013548:Sweden
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