• PMID: 25108383
• Gene Name: EXOC3
• Condition: Hypospadias
• Association: Associated
• Mutation: rs11749327
• Population size: 6492
• Population details: 1,006 boys who underwent surgery for hypospadias and 5,486 individuals (2,390 males and 3,096 females)
• Sex: Male
• Infertility type: Male infertility
• Associated genes: GWAS

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

Geller F, Feenstra B, Carstensen L, Pers TH, van Rooij IA, Körberg IB, Choudhry S, Karjalainen JM, Schnack TH, Hollegaard MV, Feitz WF, Roeleveld N, Hougaard DM, Hirschhorn JN, Franke L, Baskin LS, Nordenskjöld A, van der Zanden LF, Melbye M.

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. FAU - Geller, Frank AU - Geller F AD - Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. FAU - Feenstra, Bjarke AU - Feenstra B AD - Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. FAU - Carstensen, Lisbeth AU - Carstensen L AD - Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. FAU - Pers, Tune H AU - Pers TH AD - 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. FAU - van Rooij, Iris A L M AU - van Rooij IA AD - Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Körberg, Izabella Baranowska AU - Körberg IB AD - 1] Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. [2] Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. FAU - Choudhry, Shweta AU - Choudhry S AD - Department of Urology, University of California, San Francisco, San Francisco, California, USA. FAU - Karjalainen, Juha M AU - Karjalainen JM AD - Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands. FAU - Schnack, Tine H AU - Schnack TH AD - Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. FAU - Hollegaard, Mads V AU - Hollegaard MV AD - Danish Centre for Neonatal Screening, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark. FAU - Feitz, Wout F J AU - Feitz WF AD - Department of Urology, Pediatric Urology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Roeleveld, Nel AU - Roeleveld N AD - 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. FAU - Hougaard, David M AU - Hougaard DM AD - Danish Centre for Neonatal Screening, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark. FAU - Hirschhorn, Joel N AU - Hirschhorn JN AD - 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. FAU - Franke, Lude AU - Franke L AD - Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands. FAU - Baskin, Laurence S AU - Baskin LS AD - Department of Urology, University of California, San Francisco, San Francisco, California, USA. FAU - Nordenskjöld, Agneta AU - Nordenskjöld A AD - 1] Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. [2] Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. FAU - van der Zanden, Loes F M AU - van der Zanden LF AD - Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands.