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Common variants in DGKK are strongly associated with risk of hypospadias

A Corrigendum to this article was published on 01 March 2011

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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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  • 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.

References

  1. Fredell, L. et al. Heredity of hypospadias and the significance of low birth weight. J. Urol. 167, 1423–1427 (2002).

    Google Scholar 

  2. Schnack, T.H. et al. Familial aggregation of hypospadias: a cohort study. Am. J. Epidemiol. 167, 251–256 (2008).

    Google Scholar 

  3. Watanabe, M. et al. Haplotype analysis of the estrogen receptor 1 gene in male genital and reproductive abnormalities. Hum. Reprod. 22, 1279–1284 (2007).

    Google Scholar 

  4. Wang, Y. et al. Mutation analysis of five candidate genes in Chinese patients with hypospadias. Eur. J. Hum. Genet. 12, 706–712 (2004).

    Google Scholar 

  5. Aschim, E.L. et al. Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene. J. Clin. Endocrinol. Metab. 89, 5105–5109 (2004).

    Google Scholar 

  6. Beleza-Meireles, A. et al. Polymorphisms of estrogen receptor beta gene are associated with hypospadias. J. Endocrinol. Invest. 29, 5–10 (2006).

    Google Scholar 

  7. Beleza-Meireles, A. et al. Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias. Eur. J. Endocrinol. 158, 729–739 (2008).

    Google Scholar 

  8. Radpour, R., Rezaee, M., Tavasoly, A., Solati, S. & Saleki, A. Association of long polyglycine tracts (GGN repeats) in exon 1 of the androgen receptor gene with cryptorchidism and penile hypospadias in Iranian patients. J. Androl. 28, 164–169 (2007).

    Google Scholar 

  9. Beleza-Meireles, A., Kockum, I., Lundberg, F., Söderhäll, C. & Nordenskjöld, A. Risk factors for hypospadias in the estrogen receptor 2 gene. J. Clin. Endocrinol. Metab. 92, 3712–3718 (2007).

    Google Scholar 

  10. Thai, H.T.T. et al. The valine allele of the V89L polymorphism in the 5-alpha-reductase gene confers a reduced risk for hypospadias. J. Clin. Endocrinol. Metab. 90, 6695–6698 (2005).

    Google Scholar 

  11. Ban, S. et al. Genetic polymorphisms of ESR1 and ESR2 that may influence estrogen activity and the risk of hypospadias. Hum. Reprod. 23, 1466–1471 (2008).

    Google Scholar 

  12. van der Zanden, L.F.M. et al. Genetics of hypospadias: are single-nucleotide polymorphisms in SRD5A2, ESR1, ESR2, and ATF3 really associated with the malformation? J. Clin. Endocrinol. Metab. 95, 2384–2390 (2010).

    Google Scholar 

  13. Butcher, L.M., Davis, O.S.P., Craig, I.W. & Plomin, R. Genome-wide quantitative trait locus association scan of general cognitive ability using pooled DNA and 500K single nucleotide polymorphism microarrays. Genes Brain Behav. 7, 435–446 (2008).

    Google Scholar 

  14. Macgregor, S. et al. Highly cost-efficient genome-wide association studies using DNA pools and dense SNP arrays. Nucleic Acids Res. 36, e35 (2008).

    Google Scholar 

  15. Pearson, J.V. et al. Identification of the genetic basis for complex disorders by use of pooling-based genomewide single-nucleotide-polymorphism association studies. Am. J. Hum. Genet. 80, 126–139 (2007).

    Google Scholar 

  16. Shifman, S. et al. A whole genome association study of neuroticism using DNA pooling. Mol. Psychiatry 13, 302–312 (2008).

    Google Scholar 

  17. Lambert, J.C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer′s disease. Nat. Genet. 41, 1094–1099 (2009).

    Google Scholar 

  18. Imai, S., Kai, M., Yasuda, S., Kanoh, H. & Sakane, F. Identification and characterization of a novel human type II diacylglycerol kinase, DGK kappa. J. Biol. Chem. 280, 39870–39881 (2005).

    Google Scholar 

  19. Brouwers, M.M. et al. Hypospadias: risk factor patterns and different phenotypes. BJU Int. 105, 254–262 (2010).

    Google Scholar 

  20. Hoogendoorn, E.H. et al. Thyroid function and prevalence of anti-thyroperoxidase antibodies in a population with borderline sufficient iodine intake: influences of age and sex. Clin. Chem. 52, 104–111 (2006).

    Google Scholar 

  21. Davis, O.S.P., Plomin, R. & Schalkwyk, L.C. The SNPMaP package for R: a framework for genome-wide association using DNA pooling on microarrays. Bioinformatics 25, 281–283 (2009).

    Google Scholar 

  22. Franke, B., Arias Vasquez, A., Veltman, J.A., Brunner, H.G., Rijpkema, M. & Fernández, G. Genetic variation in CACNA1C, a gene associated with bipolar disorder, influences brainstem rather than gray matter volume in healthy individuals. Biol. Psychiat. 68, 586–588 (2010).

    Google Scholar 

  23. Spielman, R.S., McGinnis, R.E. & Ewens, W.J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 52, 506–516 (1993).

    Google Scholar 

  24. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Google Scholar 

  25. Kazeem, G.R. & Farrall, M. Integrating case-control and TDT studies. Ann. Hum. Genet. 69, 329–335 (2005).

    Google Scholar 

  26. Rothman, K.J., Greenland, S. & Lash, T.L. Modern Epidemiology (Lippincott Williams & Wilkins, Philadelphia, 2008).

Download references

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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Authors

Contributions

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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Correspondence to Barbara Franke.

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The authors declare no competing financial interests.

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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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