Common variants in DGKK are strongly associated with risk of hypospadias.
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.
Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Loes F M
LF
van der Zanden
Iris A L M
IA
van Rooij
Wout F J
WF
Feitz
Jo
J
Knight
A Rogier T
AR
Donders
Kirsten Y
KY
Renkema
Ernie M H F
EM
Bongers
Sita H H M
SH
Vermeulen
Lambertus A L M
LA
Kiemeney
Joris A
JA
Veltman
Alejandro
A
Arias-Vásquez
Xufeng
X
Zhang
Ellen
E
Markljung
Liang
L
Qiao
Laurence S
LS
Baskin
Agneta
A
Nordenskjöld
Nel
N
Roeleveld
Barbara
B
Franke
Nine V A M
NV
Knoers
D019852:Diacylglycerol Kinase / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007021:Hypospadias / Q000235:genetics*; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D019852:Diacylglycerol Kinase