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

Nature Genetics volume 46, pages 957–963 (2014)Cite this article

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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 × 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.

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Figure 1: Graphical display of the GRAIL results.
Figure 2: DEPICT analysis.
Figure 3: Graphical display of DEPICT gene set enrichment analysis.

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Acknowledgements

We thank all study participants (as well as their parents) in Denmark, the Netherlands, Sweden and the United States for their cooperation in this study. We would also like to thank everyone involved in data collection and biological material handling in the four study groups (C.H.W. Wijers, S. van der Velde-Visser, K. Kwak, J. Knoll, R. de Gier, B. Kortmann, A. Paauwen, H.G. Kho, J. Driessen and the anesthesiologists of OR 18 for the Dutch group; data collection in the Netherlands was performed as part of a PhD project supported by the Radboud University Medical Center).

B.F. is supported by an Oak Foundation fellowship. T.H.P. is supported by the Danish Council for Independent Research Medical Sciences (FSS) and the Alfred Benzon Foundation. The study was supported by an FSS grant (0602-01455B), the Novo Nordisk Foundation, the Lundbeck Foundation (421/06), the Swedish Research Council, Foundation Frimurare Barnhuset Stockholm, the Stockholm City Council, the Swedish Society for Medical Research and Karolinska Institutet. Funding support for expression analysis performed at the University of California, San Francisco came from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-sponsored K12 Urologic Research (KURe) program (5K12DK083021). The funders had no role in study design, execution or analysis or in manuscript writing.

Author information

Authors and Affiliations

  1. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark

    Frank Geller, Bjarke Feenstra, Lisbeth Carstensen, Tine H Schnack & Mads Melbye

  2. Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA

    Tune H Pers & Joel N Hirschhorn

  3. Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA

    Tune H Pers & Joel N Hirschhorn

  4. Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

    Tune H Pers & Joel N Hirschhorn

  5. Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark

    Tune H Pers

  6. Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands

    Iris A L M van Rooij, Nel Roeleveld & Loes F M van der Zanden

  7. Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden

    Izabella Baranowska Körberg & Agneta Nordenskjöld

  8. Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

    Izabella Baranowska Körberg & Agneta Nordenskjöld

  9. Department of Urology, University of California, San Francisco, San Francisco, California, USA

    Shweta Choudhry & Laurence S Baskin

  10. Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands

    Juha M Karjalainen & Lude Franke

  11. Department of Clinical Biochemistry, Danish Centre for Neonatal Screening, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark

    Mads V Hollegaard & David M Hougaard

  12. Department of Urology, Pediatric Urology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands

    Wout F J Feitz

  13. Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands

    Nel Roeleveld

  14. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA

    Joel N Hirschhorn

  15. Department of Medicine, Stanford School of Medicine, Stanford, California, USA

    Mads Melbye

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  1. Frank Geller
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Contributions

F.G., B.F. and M.M. wrote the first draft of the manuscript. F.G., B.F., L.C. and T.H.P. analyzed the data. I.A.L.M.v.R., I.B.K., T.H.S., M.V.H., W.F.J.F., N.R., D.M.H., A.N. and L.F.M.v.d.Z. contributed by collecting phenotype data and/or setting up the samples for genotyping. T.H.P., J.M.K., J.N.H. and L.F. developed the DEPICT analysis. S.C. and L.S.B. planned, performed and analyzed the expression experiment. F.G., B.F. and M.M. planned and supervised the work. All authors contributed to writing the final manuscript.

Corresponding author

Correspondence to Frank Geller.

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Geller, F., Feenstra, B., Carstensen, L. et al. Genome-wide association analyses identify variants in developmental genes associated with hypospadias. Nat Genet 46, 957–963 (2014). https://doi.org/10.1038/ng.3063

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