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

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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.

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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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