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Nat Genet. 2014 Sep;46(9):957-63. doi: 10.1038/ng.3063. Epub 2014 Aug 10.

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

Author information

1
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
2
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.
3
Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands.
4
1] Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. [2] Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
5
Department of Urology, University of California, San Francisco, San Francisco, California, USA.
6
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
7
Danish Centre for Neonatal Screening, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark.
8
Department of Urology, Pediatric Urology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
9
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.
10
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.
11
1] Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. [2] Department of Medicine, Stanford School of Medicine, Stanford, California, USA.

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.

PMID:
25108383
DOI:
10.1038/ng.3063
[Indexed for MEDLINE]

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