Abstract
Hypospadias is a common congenital malformation of the male external genitalia. We performed a genome-wide association study using pooled DNA from 436 individuals with hypospadias (cases) and 494 controls of European descent and selected the highest ranked SNPs for individual genotyping in the discovery sample, an additional Dutch sample of 133 cases and their parents, and a Swedish series of 266 cases and 402 controls. Individual genotyping of two SNPs (rs1934179 and rs7063116) in DGKK, encoding diacylglycerol kinase κ, produced compelling evidence for association with hypospadias in the discovery sample (allele-specific odds ratio (OR) = 2.5, P = 2.5 × 10−11 and OR = 2.3, P = 2.9 × 10−9, respectively) and in the Dutch (OR = 3.9, P = 2.4 × 10−5 and OR = 3.8, P = 3.4 × 10−5) and Swedish (OR = 2.5, P = 2.6 × 10−8 and OR = 2.2, P = 2.7 × 10−6) replication samples. Expression studies showed expression of DGKK in preputial tissue of cases and controls, which was lower in carriers of the risk allele of rs1934179 (P = 0.047). We propose DGKK as a major risk gene for hypospadias.
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Change history
24 February 2011
In the version of this article initially published, the third and fourth column headings in Table 2 were mislabeled and the abbreviations in the footnotes of Table 2 were inadvertently duplicated. The correct heading for the third column is "T" and the correct heading for the fourth column is "NT". These errors have been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank all cases and parents for their cooperation in this study. We are grateful to the Microarray Facility Nijmegen of the Department of Human Genetics (RUNMC), in particular to M. Steehouwer, for performing the microarray experiments, and to T. Vrijenhoek and J. Hehir-Kwa for their assistance in data analysis. We would also like to thank everyone involved in the data collection, S. van der Velde-Visser, C. Beumer, K. Kwak, J. Knoll, R. de Gier, B. Kortmann, A. Paauwen, K. Kho, J. Driessen and the anesthesiologists of OR 18. Finally, we are grateful to M. Coenen, J. Groothuismink, R. Makkinje and M. Schijvenaars for their practical guidance. This research is performed within a PhD project supported by the Radboud University Nijmegen Medical Centre and with extra budget from the Urology Foundation 1973. J. Knight is funded by the Department of Health through the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's and St. Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust.
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L.F.M.v.d.Z. was the principal investigator who conducted the study. I.A.L.M.v.R., N.R., B.F. and N.V.A.M.K. designed the study and obtained financial support. L.F.M.v.d.Z., I.A.L.M.v.R., W.F.J.F., K.Y.R., E.M.H.F.B., S.H.H.M.V., L.A.L.M.K., N.R., B.F. and N.V.A.M.K. were involved in the collection of the discovery sample and the Dutch replication sample. J.A.V., A.A.-V. and B.F. collected the in-house controls. X.Z., E.M. and A.N. were responsible for the collection of the Swedish replication sample. L.Q. and L.S.B. collected the prepuce samples and performed the expression studies. L.F.M.v.d.Z. conducted all statistical analyses in collaboration with I.A.L.M.v.R., J.K. and A.R.T.D. L.F.M.v.d.Z. took primary responsibility for drafting the manuscript, with intellectual contributions, editing and approval from all other authors.
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van der Zanden, L., van Rooij, I., Feitz, W. et al. Common variants in DGKK are strongly associated with risk of hypospadias. Nat Genet 43, 48–50 (2011). https://doi.org/10.1038/ng.721
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DOI: https://doi.org/10.1038/ng.721
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