Common variants in DGKK are strongly associated with risk of hypospadias

van der Zanden, Loes F. M. and van Rooij, Iris A. L. M. and Feitz, Wout F. J. and Knight, Jo and Donders, A. Rogier T. and Renkema, Kirsten Y. and Bongers, Ernie M. H. F. and Vermeulen, Sita H. H. M. and Kiemeney, Lambertus A. L. M. and Veltman, Joris A. and Arias-Vásquez, Alejandro and Zhang, Xufeng and Markljung, Ellen and Qiao, Liang and Baskin, Laurence S. and Nordenskjöld, Agneta and Roeleveld, Nel and Franke, Barbara and Knoers, Nine V. A. M. (2011) Common variants in DGKK are strongly associated with risk of hypospadias. Nature Genetics, 43 (1). pp. 48-50. ISSN 1061-4036

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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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Nature Genetics
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07 Jun 2016 10:06
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22 Nov 2022 03:22